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PHYSIOLOGICAL REVIEWS Vol. 78 No. 4 October 1998, pp. 1165-1191
Copyright ©1998 by the American Physiological Society
Departments of Molecular and Integrative Physiology, Medicine, and Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas
I. INTRODUCTION
II. GENETIC FACTORS
III. MORPHOLOGY
IV. ANIMAL AND CELL MODELS
V. ABNORMALITIES IN FUNCTION IN THE POLYCYSTIC KIDNEY
VI. CYST FLUID
A. Composition
B. Exchange With the Circulation
VII. CYST GROWTH
A. In Vivo
B. Cyst Formation by Cultured Cells
VIII. TRANSPORT MECHANISMS INVOLVED IN FLUID SECRETION
A. Madin-Darby Canine Kidney Cell Model
B. Autosomal Dominant Polycystic Kidney Disease Tissue
IX. ABSORPTION BY THE CYSTIC EPITHELIUM
X. DILEMMA POSED BY THE GRADIENT CYST
XI. HEPATIC CYSTS IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
XII. A CYST ACTIVATING FACTOR PRESENT IN CYST FLUID
XIII. QUESTIONS REMAINING
XIV. COMPARISON OF THE CYSTIC CELL TO OTHER EPITHELIAL CELLS
A. Renal Epithelial Cells
B. Intestinal Crypt and Lung Cells
XV. CONCLUSIONS
REFERENCES
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Sullivan, Lawrence P., Darren P. Wallace, and Jared J. Grantham. Epithelial Transport in Polycystic Kidney Disease. Physiol. Rev. 78: 1165-1191, 1998. 
In autosomal dominant polycystic kidney disease (ADPKD), the genetic defect results in the slow growth of a multitude of epithelial cysts within the renal parenchyma. Cysts originate within the glomeruli and all tubular structures, and their growth is the result of proliferation of incompletely differentiated epithelial cells and the accumulation of fluid within the cysts. The majority of cysts disconnect from tubular structures as they grow but still accumulate fluid within the lumen. The fluid accumulation is the result of secretion of fluid driven by active transepithelial Cl
secretion. Proliferation of the cells and fluid secretion are activated by agonists of the cAMP signaling pathway. The transport mechanisms involved include the cystic fibrosis transmembrane conductance regulator (CFTR) present in the apical membrane of the cystic cells and a bumetanide-sensitive transporter located in the basolateral membrane. A lipid factor, called cyst activating factor, has been found in the cystic fluid. Cyst activating factor stimulates cAMP production, proliferation, and fluid secretion by cultured renal epithelial cells and also is a chemotactic agent. Cysts also appear in the intrahepatic biliary tree in ADPKD. Normal ductal cells secrete Cl and HCO3. The cystic ductal cell also secretes Cl, but HCO3 secretion is diminished, probably as the result of a lower population of Cl/HCO3 exchangers in the apical membrane as compared with the normal cells. Some segments of the normal renal tubule are also capable of utilizing CFTR to secrete Cl, particularly the inner medullary collecting duct. The ability of Madin-Darby canine kidney cells and normal human kidney cortex cells to form cysts in culture and to secrete fluid and the functional similarities between these incompletely differentiated, proliferative cells and developing cells in the intestinal crypt and in the fetal lung have led us to suggest that Cl and fluid secretion may be a common property of at least some renal epithelial cells in an intermediate stage of development. The genetic defect in ADPKD may not directly affect membrane transport mechanisms but rather may arrest the development of certain renal epithelial cells in an incompletely differentiated, proliferative stage.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the appearance and slow growth of fluid-filled cysts within the parenchyma of the kidney. The cysts begin as focal microscopic enlargements or diverticula at almost any point along the nephron (7, 103, 120). As the cysts enlarge, they begin to distort the renal parenchyma. Blood vessels and functioning nephrons are pushed aside, and remodeling of the extracellular matrix occurs. Over a period of decades, the growth of the cysts enlarges the kidney to four to six times its normal size, but the number of functioning nephrons declines and renal failure progresses. In the end-stage kidney, most of the renal parenchyma has been replaced by cysts and fibrotic tissue. The course of the disease varies widely. It usually becomes clinically apparent in the third to seventh decade of life, although it has been found in the fetus and in children on occasion. Approximately one-half of the patient population will progress to chronic renal failure and require replacement therapy. Other abnormalities appear in some patients. These include vascular aneurysms and the appearance of cysts in the biliary tracts within the liver. Autosomal dominant polycystic kidney disease is one of the most common, potentially lethal, genetic diseases known, occurring with a frequency of 1 in 1,000 births worldwide (52, 56). There is a recessive form of the disease (ARPKD) that is usually lethal within the first year of life and an acquired form that is often seen in patients undergoing chronic dialysis treatment. There are other diseases that produce cysts in the kidney, and this has made it difficult to interpret the literature written before the inheritable forms were fully recognized and classified (12). Autosomal dominant polycystic kidney disease is emphasized in this review. In the autosomal dominant form of the disease, the genetic mutations do not appear to interfere with the normal development of the kidney. Glomerular function usually appears to be normal well into adult life, and changes in tubular function are relatively slight. However, in a minority of developed nephrons, cysts begin to form as a single tubular cell, or a small, localized group of cells begins to proliferate. The initiating factor is unknown. It has been postulated that in the process of repair of a localized injury, the replacement of damaged cells goes awry (67). The regulation of proliferation and differentiation of new cells is apparently abnormal, and proliferation of relatively undifferentiated cells proceeds indefinitely. This can occur at any point from Bowman's capsule to the terminal collecting duct. The proliferating cells initially may cause a bulge in the tubule or may form an out pocket or diverticulum in the wall of the tubule. As the cysts develop and fill with fluid, the adjoining extracellular matrix undergoes remodeling. The basement membrane may thicken or become laminated, and inflammation and fibrogenesis occur in the later stages of the disease. Studies of the function of the polycystic kidney have uncovered abnormalities in the ability to osmotically concentrate urine, to respond to an acid challenge, and to correct extracellular fluid volume expansion. The cause of these abnormalities has not been pursued extensively. However, the transport functions of cystic cells and the mechanisms of fluid accumulation within the cysts have been investigated in detail because it is considered that cyst growth is a major factor in the progress to renal failure. Describing the results of these investigations is the object of this review. Research into this complex disease has raised questions about the function and structure of genes and the proteins for which they are responsible; about tubular morphology; cellular proliferation and differentiation; formation of basement membrane and the interstitial matrix; inflammation, hormonal, paracrine, and autocrine factors; and signal transduction mechanisms. All of these questions may have bearing on the abnormalities of epithelial transport, but a review of all of these subjects is impractical. We have attempted to limit the review to a short description of the new genetic findings, which do not yet indicate a direct link to transport mechanisms, and to those investigations that directly bear on the function of the cystic epithelium. Progress in understanding the genetics of ADPKD has been remarkable in the last decade. Mutations of three different genes can produce forms of the disease. The first gene PKD1 is located on chromosome 16 (16p13.3), and mutations of it account for ~85% of the cases of ADPKD (143). It contains 52 kb of DNA that encode a 14-kb mRNA transcript and a protein, polycystin I, a molecule weighing 460 kDa and consisting of ~4,300 amino acids. The protein contains several putative membrane-spanning regions and extracellular domains that are analogous to those found in cell-to-cell or cell-to-matrix proteins. These include four fibronectin-related domains, leucine-rich repeats, and C-type lectins (1, 23, 47, 87, 91). Polycystin I is highly expressed in the developing kidney; it is expressed in low amounts or not at all in the adult kidney, but some reports indicate that it is overexpressed in cyst epithelial cells. Attempts at localizing it within renal cells has produced variable results (65, 78, 90, 130, 174, 175). The PKD2 gene is located on chromosome 4 (4q23-p23). It also encodes a large protein, polycystin II, of ~110 kDa with a section that is homologous to PKD1 (99, 121). Mutations of this gene account for 10-15% of patients with ADPKD. It is hypothesized that the COOH-terminal tails of polycystin I and II interact, but colocalization of the two proteins within cells has not yet been demonstrated (141, 172). The onset of end-stage renal disease usually occurs later in the life of patients with the PKD2 genotype (56, 131). Mutations of a third gene, whose structure has not been determined, account for a small percentage of the patient population (39). Most of the mutations that have been found to occur in the PKD1 and PKD2 genes appear to inactivate the genes (24). In ADPKD, every kidney cell contains a mutated allele, yet cysts appear in only a small fraction of nephrons. It is postulated that random somatic mutations of the wild-type allele occur in some cells, and this results in clonal growth of cells. Evidence for this loss of heterozygosity in cells forming the cysts has been obtained in patients with the PKD1 genotype. This "second hit" hypothesis may also account for the highly variable course of the disease among family members with the same germ-line mutation (17, 24, 140). The little information that is available on the genesis of the cysts strongly suggests that the polycystin proteins play a role in proliferation and differentiation of renal epithelial cells. The ongoing studies of the function of these proteins are likely to provide major insights into these processes and the development of the nephrons. There is as yet no evidence of a direct link of these proteins to transport mechanisms. In examining the literature on the morphology of the ADPKD kidney, the major questions considered were as follows: 1) At what sites along the tubule do cysts appear? 2) Does the appearance of the cells lining the cysts offer clues on the site of origin of the cyst or on the process of cyst development? 3) Are the cysts connected to functioning tubules or glomeruli that provide the fluid contained within the cyst? Early anatomic studies of the cystic kidney did not produce consistent results. Some did not fully distinguish among the various types of diseases that cause cysts to appear in the kidney (138). Later studies of adult polycystic kidneys, from patients whose family history indicated an hereditary connection, dealt mostly with the end-stage kidney in which the parenchyma is grossly altered by the cysts and is extensively fibrotic (86, 103). Using Peter's reconstruction method (137), Lambert (103) reported that cysts were found in Bowman's capsule, in all sections of the nephron, and in the collecting tubules. None of the examined glomerular cysts was connected to patent nephrons, and most contained glomerular capillary tufts that were slightly reduced in size but appeared to be functional. A minority of tubular cysts existed as termination of nephrons with normal glomeruli; the rest were connected to patent tubules. Most of the cysts found in collecting tubules were also connected to patent tubules. Lambert's use of Peter's graphical reconstruction method may have led him to concentrate primarily on quite small cysts. Using a microdissection technique, Heggo (86) also found that cysts appeared in the glomeruli and all sections of the tubules. They were most numerous in the glomeruli, in the angle of the loop of Henle, and especially in the collecting tubules. Heggo noted that cysts frequently occurred at the bifurcations of the collecting tubule and that abnormalities of collecting tubule branching occurred. No mention was made of the number of cysts with connections to patent tubules. Baert (7) was able to obtain kidneys from two patients that were in the early stage of disease. Glomerular function was normal in both cases. Approximately 100 nephrons and 20 collecting tubules were microdissected from each kidney. Cysts were randomly distributed throughout the glomeruli and the tubules; all the cysts in these early stage kidneys were connected to tubules. No abnormal branching of the collecting tubules was noted. It should be pointed out that the site of location of cysts that have lost tubular connections cannot be identified by microdissection, and these cysts would probably be ignored in the process of dissection. Transmission electron microscopy studies of cyst walls indicated a reduction or disappearance of microvilli and reduced basolateral infoldings and intracellular organelles. Polyps were frequently present in the examined cysts, and the tubular basement membrane was thickened and, in many cases, laminated. Interstitial fibrosis was often noted (13, 35, 49, 55). Scanning electron microscopy investigations provided much more detail (34, 48, 50, 70). The appearance of the cystic epithelium varied widely among cysts from the same kidney; the cells of some cysts bore a close resemblance to normal tubular or glomerular epithelial cells, whereas most did not (Fig. 1). A few exhibited distinct signs of hyperplasia in the form of micropolyps, adenomas, or linear cordlike projections (13, 50, 70). In a study of 387 cysts in ADPKD kidneys from 10 patients (70), the epithelium of the large majority of cysts was not typical of that of a normal tubular segment (Table 1). The appearance of the apical surface suggested that dedifferentiation had occurred (Fig. 1B). The epithelium of a small minority of cysts resembled that of various tubular segments. About 5% of the cysts were distinctly hyperplastic. All of these various types of cystic epithelium were found in at least four of the kidneys examined, with the exception of the cysts in which the epithelium resembled that of the proximal tubule. A detailed analysis of cell size and number and cyst size clearly indicated that proliferation of cells occurred as the cysts expanded; the cysts were not caused by a simple ballooning of the tubule. Because a few cysts contained cells of more than one phenotype, it cannot be unequivocally concluded that proliferation occurred by clonal growth from a single cell. Examination of a single half of 259 bisected cysts found tubular openings in only 25. An additional examination of both halves of 11 bisected cysts uncovered tubular openings in 3. Thus fluid can accumulate within the majority of the cysts only by secretion across the cystic epithelium (70).
All of these morphological studies have focused on the cysts. There do not appear to be any detailed studies of cellular architecture in noncystic segments of the tubules in ADPKD kidneys, although all the tubular cells presumably carry the mutated gene. This information will be difficult to obtain, since the studies must be performed on renal tissue removed from patients that have not reached the end stage of renal failure. In conclusion, cysts may develop at any point from Bowman's capsule to the terminal collecting duct. Only a small minority of the tubules are involved. Cyst growth is accompanied by proliferation of cells that are usually poorly differentiated. The large majority of the cysts are lined by cells not resembling any normal tubular phenotype. At some point in their development, the majority of cysts lose their tubular connection. Accumulation of fluid within these cysts after that point must occur by secretion across the cystic epithelium. Several animal models of polycystic disease have been discovered or developed, and these have been extensively reviewed (33, 64, 79, 119). The murine models especially have been used extensively to study the genetic and environmental factors that modify disease progression. However, very little information on function is available in these models. The Han:SPRD rat has been a particularly useful model. Discovered in Hanover, Germany in 1989, the spontaneous mutation in the Sprague-Dawley strain resulted in a slowly progressive, autosomal dominant disease with many of the characteristics of the human disease (34, 64, 95, 96, 146). However, the results of recent studies indicate that the mutation is not in the PKD1 or PKD2 genes (14, 122). The homozygous (cy/cy) rat develops massively enlarged cystic kidneys, profound azotemia, and dies at about 3 wk of age. There have been no reports as yet of patients that were known to be homozygous for mutations of PKD1 or PKD2; however, ADPKD can be severe in the fetus and in young children, and the homozygous fetus may not survive in utero. Cysts in the kidney of the heterozygote rat (cy/+) enlarge over many months. The disease is more severe, and life expectancy is less in the male rat than in the female, a characteristic also of the human form of the disease (52). Transgenic models of polycystic kidney disease have also been developed. Renal cysts appear in transgenic mice developed with the use of simian virus 40 (SV40)-early region with large-T antigen and in mice made transgenic by using a c-myc oncogene driven by an SV40 enhancer and a human Cultured cell models of renal cysts have been developed and studied intensively with the objective of understanding the mechanisms involved in cyst growth and in the accumulation of fluid within the cysts. These include a subtype of Madin-Darby canine kidney (MDCK) cells (64, 110, 111, 118), primary cultures of human kidney cortex (HKC) cells (123), and primary cultures of ADPKD cyst cells (75, 113, 159). This began after McAteer et al. (118) discovered that fluid-filled cysts will develop by clonal growth when wild-type MDCK cells are seeded within a collagen matrix. Isolation of a single cyst and culture of the cells forming that cyst resulted in the development of a subtype of MDCK cells that reproducibly and efficiently formed cysts (73). Techniques were developed for measuring fluid transport into the cultured cysts and changes in cell volume (165). Microelectrode techniques were applied (108), and epifluorimetric methods were adapted for measuring cellular fluid composition (158). A method of measuring fluid transport by monolayers of these cells grown on a permeable support was developed (73, 124), and Ussing chamber methods have been used to study the transport properties of the cells (75, 113). Glomerular filtration rate (GFR) in the polycystic kidney disease patient may remain in the normal range long after cysts are discernable by radiologic or sonigraphic techniques. Clearance of p-aminohippurate ( PAH ) and GFR may also remain in the normal range after development of hypertension, but the filtration fraction may be elevated (170). However, the polycystic kidney disease patient with a normal GFR commonly exhibits a reduced ability to maximally concentrate the urine (30, 37, 58, 116, 139). In one comprehensive study, 177 nonazotemic subjects with ADPKD and 123 unaffected family members were subjected to 12 h of water deprivation and an injection of vasopressin (58). Maximum urine osmotic concentration averaged 680 ± 14 mosmol/kgH2O in the first group and 812 ± 13 mosmol/kgH2O in the second group. Examination of the cause of defective concentrating ability uncovered a variable capacity to increase free water reabsorption under conditions of increasing osmolar clearance by ADPKD patients with normal filtration rates (37, 116). However, the ability to increase free water clearance with increasing delivery of filtrate to the distal nephron was not affected in one study (116). These results suggest that salt reabsorption by the thick ascending limb is not impaired but that water reabsorption from the collecting tubule may be defective. These results could be attributed to an effect of medullary cyst growth on the architecture of the medulla, resulting in altered function of the countercurrent mechanism, or to an effect of cortical cysts on medullary blood flow rate or the delivery of tubular fluid to long loops of Henle. It is also possible that the cellular response to vasopressin is defective. Examination of the expression of water channels in the ADPKD kidney has not disclosed an absence or mislocalization of aquaporin (AQP)-2, the water channel regulated by vasopressin (6, 42, 85) or of AQP-3, the water channel found in the basolateral membrane of principal cells in the collecting tubule (85). However, Western immunoblot analysis showed a decline in AQP-2 content in early stage ADPKD kidneys and abnormalities in glycosylation patterns (42). More research is necessary to determine if this is the cause of the abnormality in concentrating ability. In particular, the collecting tubules rather than the cysts should be the focus for examination. A concentrating defect has not yet been documented in the Han:SPRD rat. However, proton NMR studies of renal tissue from normal and heterozygous rats have indicated reduced concentrations of the osmolytes betaine, taurine, and glycerophosphocholine but not inositol in the heterozygous animal. These osmolytes normally accumulate in medullary cells when the environment is hypertonic. The osmotic concentration of the urine in the two groups did not differ; however, these rats did not undergo water deprivation and vasopressin injection (128). A concentrating defect was also found to be present in the diphenylthiazole-treated rat model in the presence of normal GFR (27, 28). The ability to dilute the urine was not impaired. Micropuncture experiments indicated no change in proximal or distal tubular fluid-to-plasma ratios of inulin concentration or in the distal tubular fluid-to-plasma osmotic concentration ratio in rats treated for 4 days with diphenylthiazole. However, the Na+ concentrations in medullary and papillary tissue slices were reduced, and microscopic changes in the morphology of collecting tubular cells occurred. It was concluded that the defect in concentrating ability was because of impaired water transport by the collecting tubular epithelium (28). A later study indicated that the rise in medullary adenylate cyclase activity, caused by administration of vasopressin, was reduced in diphenylthiazole-treated rats (43). The relevance of these studies to the ADPKD concentrating defect is not known. The natriuretic response to volume expansion in ADPKD patients has been reported to be blunted (37) or exaggerated (38). In a study comparing ADPKD patients with normal GFR to normal control subjects, Torres et al. (170) found that baseline fractional excretion of Na+ was higher in the patients, although absolute rates of excretion were similar between the two groups. The filtration fraction was also higher in the patients in the baseline period. During saline infusion, fractional Na+ excretion also increased to a greater extent in the patients. The curve relating natriuresis to arterial pressure was shifted to the right in the hypertensive ADPKD patients but not in the normotensives. Plasma renin levels tended to be higher and aldosterone levels lower in the hypertensive patients before expansion, and both levels fell in response to volume expansion. Atrial natriuretic factor (ANF) levels did not differ from control subjects (170). A similar shift in the pressure-natriuresis curve was reported in ADPKD patients with chronic expansion (147). The question arises, Is the alteration in the reabsorption of Na+ due to an intrinsic alteration in tubular transport mechanisms or to an alteration in control mechanisms? Hypertension is common among patients with ADPKD, and its development usually precedes reduction in renal function. In a comparison of hypertensive to normotensive ADPKD patients with normal GFR, Bell et al. (10) found no differences in plasma volume, a greater increase in cardiac index with exercise, increased renal vascular resistance, and higher ANF levels in the hypertensive patients. Renin and aldosterone levels were not different. However, use of an angiotensin-converting enzyme (ACE) inhibitor during a high-sodium diet increased renin levels only in the hypertensive patients. Torres et al. (169) performed an additional comparison of the response of hypertensive ADPKD patients and normotensive control subjects to volume expansion. The results confirmed that hypertensive patients with ADPKD have lower renal plasma flow, higher renal vascular resistance and filtration fraction, and an altered pressure-natriuresis relationship during volume expansion. Administration of an ACE inhibitor increased renin secretion and renal plasma flow, reduced renal vascular resistance and filtration fraction, and restored the pressure-natriuresis relationship to normal. In a study that compared the effects of ACE inhibition on hypertensive ADPKD patients and on patients with essential hypertension (29), the former exhibited higher plasma renin and aldosterone levels and responded to ACE inhibition with a greater increase in renin secretion. Long-term ACE inhibition also increased renal plasma flow and decreased filtration fraction in the ADPKD patients. Renal angiography has indicated that peripheral renal vessels are attenuated in ADPKD (32, 46). An immunocytochemistry study of ADPKD kidneys demonstrated an increase in renin-containing cells in the juxtaglomerular apparatus, persistence of renin-containing cells in atrophied glomeruli, and an increase of these cells in proximal afferent arterioles and intralobular arteries (66). Thin, attenuated arterioles in the wall of cysts often contained these cells, and they were also found in connective tissue separate from the arterial tree. Thus it is reasonable to suggest that intrarenal levels of renin are increased despite the fact that circulating levels of renin may not differ between normotensive and hypertensive ADPKD patients (28). Therefore, it seems likely that alterations in Na+ excretion in ADPKD are the result of changes in the control mechanisms and that a defect in tubular Na+ transport mechanisms may not be present. Preuss et al. (139) reported that two of four ADPKD patients given an acid challenge could not reduce urine pH and increase ammonium excretion to the same extent as control subjects. A similar finding in three of six patients was reported by Milutinovic et al. (120). Martinez-Maldonado (115), however, reported that the ability of four ADPKD patients to reduce urine pH was normal. In a more extensive study of ADPKD patients and a control group of subjects, Torres et al. (168) found that only one of eight patients could not reduce urine pH below 5.3. No significant differences existed between the ADPKD patients and control subjects. However, the ability of the patients to increase ammonium excretion in response to an acid challenge was reduced. To determine if a defect in proton secretion existed in the collecting tubules of these patients, they measured the urine to blood PCO2 difference during diuresis caused by infusion of NaHCO3 and found no significant impairment. They also measured the concentration of ammonium in cyst fluid of nine patients in an attempt to determine if a gross defect existed in ammonium production. The concentration of ammonium in nongradient cysts (cysts containing fluid with a Na+ concentration and pH similar to plasma) was higher than that reported in renal venous blood of normal subjects. Ammonium concentration was higher and urine pH lower in gradient cysts (cysts with a low Na+ concentration and a low pH). The calculated concentration of the base, NH3, in cyst fluid of the two types of cyst did not differ but that level was higher than that usually measured in renal venous blood. The authors considered this to be circumstantial evidence indicating that ammonium production is not reduced in ADPKD. They pointed out the role of the countercurrent system in the excretion of ammonium and suggested that disruption of the medullary architecture may decrease the efficiency of this system and account for the reduced ability to excrete ammonium. Organic anion secretion has been examined in the Han:SPRD rat (163). In 7- to 16-wk-old heterozygous rats, GFR and the maximal rate of PAH secretion did not vary from that of healthy control littermates. Examination of proximal cysts in vivo using fluorescence microscopy indicated that 27 of 29 cysts secreted sulfonefluorescein, which is transported by the organic anion system. Secretion of PAH has been shown to generate fluid secretion in isolated segments of rabbit proximal straight tubules (71). However, micropuncture examination of segments of superficial proximal tubules or cysts, isolated by upstream and downstream wax blocks, failed to show fluid secretion when PAH was infused intravenously (163). A. Composition
A number of studies have focused on the composition of cyst fluid as a means of understanding the properties of the lining epithelium and the origin of the fluid (15, 59-61, 88, 182). As noted initially by Gardner (59), cysts can be divided into two categories: nongradient or proximal cysts and gradient or distal cysts. This categorization is based primarily on the Na+ concentration of their fluids as related to normal plasma values. However, the terms also apply to other common tubular fluid constituents. Cyst fluids with a low Na+ concentration tend to have high K+ and H+ concentrations and low Cl All the reports of cyst fluid osmolality indicate that the values fall into a range that is close to plasma osmolality. However, the gradient cyst values were somewhat higher than those of nongradient cysts in one study: 312 vs. 285 mosmol/kgH2O (60). The low Na+ and Cl B. Exchange With the Circulation
The fluid within each cyst is not a stagnant pool. Jacobsson et al. (92) found that 2-5 h after intravenous injection of tritiated water, the concentration in cyst fluid averaged 88% of the concentration in plasma. The average turnover was more rapid in smaller cysts than in the larger. However, even in cysts with volumes greater than 10 ml, the mean value for tritiated water concentration was 82% of the plasma level. The cyst walls also exhibit some permeability to much larger molecules. An early study by Lambert (103) and a second by Bricker and Patton (19) indicated that inulin entered the cyst fluid of the majority of cysts studied. They attributed this to filtration into cysts connected to glomeruli, but a later study by Wickre and Bennett (182) of a single, nonuremic patient found that the amount of inulin recovered in cyst fluid would require a single nephron GFR of 68-250 times the normal value. Technetium-labeled diethylenetriaminepentaacetic acid (DPTA), 131I-hippurate, and PAH also entered cysts in amounts too large to be due to filtration. The DPTA is not secreted by normal proximal tubules, but it is possible that hippurate and PAH were actively secreted into the cyst cavity. Infections commonly occur in cystic tissue, and it became apparent that treatment may require the use of antibiotics that will reach an effective concentration within cyst fluid. Many will penetrate the cyst wall, some of these are weak electrolytes, and accumulation within cysts appears to depend on pH gradients. Clindamycin and metronidazole, for example, are cationic, lipid-soluble drugs that will accumulate in gradient cysts that contain fluid with a low pH (150). Penicillin derivatives evidently enter cysts very slowly, suggesting that the organic anion secretion mechanism functions poorly in many proximal cysts (11). An electron microscopic study of cyst walls provided a morphological basis for the evident large permeability of nongradient cysts and for the difference between nongradient and gradient cysts (35). Eleven of 13 nongradient cysts from 5 patients were lined by epithelia with open or short, closed zonulae occludens that were permeable to lanthanum. The fluid from the two remaining nongradient cysts, each from different patients, contained Na+ concentrations equal to or greater than serum concentrations. However, unlike the other nongradient cysts, the fluid-to-serum glucose concentration ratios were substantially less than one (0.07 and 0.17). The epithelia of these cysts possessed "tight" junctions with fusion of the outer lamellae of the plasma membranes of adjacent cells for a length of at least 50 nm. Thus, in those nongradient cysts with glucose concentrations close to that of serum, glucose may have penetrated through the leaky zonulae occludens. All seven of the gradient cysts (fluid-to-serum Na+ concentration ratios <0.4) exhibited long, closed junctions between adjacent cells that were impermeable to lanthanum (35). Gardner et al. (60) confirmed that the average fusion depth of the zonula occludens differed between nongradient and gradient cysts, 37 vs. 204 nm. A. In Vivo
Microdissection of human polycystic kidneys in an early stage of the disease revealed that small cysts look like a ballooning in a bicycle inner tube or a knob in the sidewall of a tire (7). Indeed, an early hypothesis of cyst formation proposed that the tubular basement membrane is abnormally compliant (28, 43). A study of the relationship between tubular hydrostatic pressure and outer diameters of segments of rabbit tubules had shown that the compliance of the normal basement membrane would maintain tubular diameter well below 100 µm at pressures up to 60 cmH2O or 44 mmHg (179). These pressures are higher than those recorded in vivo within cysts of ADPKD patients and in the cystic nephrons of rats treated with nordihydroguaiaretic acid (16, 48). However, it was considered possible that defective formation of the basement membrane could result in tubular expansion at normal or even less than normal intratubular pressures. To investigate this hypothesis, Welling and Welling (180) developed mass balance equations for fluid movement into and out of the cysts by filtration, secretion, absorption, and distal outflow. An initial postulate of a constant and normally transporting cellular and basement membrane mass in the stretching cyst was obviously untenable on geometric grounds, since the tubular wall would become impossibly thin at cyst diameters beyond 1 mm. Cellular growth or hyperplasia must be invoked to explain the size of cysts routinely seen in cystic kidneys. However, they also showed that cyst growth would stop when the absorptive capacity of the hyperplastic tubular wall rose to equal the inflow (filtration) rate. In a cyst in which distal outflow is totally obstructed and each added cell absorbs at a normal rate, the spherical diameter would not increase beyond 2 mm. Additional cyst growth beyond that point would require a reduction in the absorptive capacity of the lining cells (180). Thus a combination of proliferation of cells with a low reabsorptive capacity and an abnormally compliant basement membrane could conceivably lead to cyst formation, particularly if a downstream obstruction increased tubular pressure. Tubular obstruction, caused by polyps appearing on the inner tubular wall, has been considered to be an initiating factor in the dilatation of a tubule and the subsequent formation of a cyst. Polyps have been observed in ADPKD cysts and on occasion are found at a position suggesting that they may obstruct an outflow pathway (13, 49, 50). Polyps that impinged on outflow lumens of collecting tubular cysts were found in rats treated with nordihydroguaiaretic acid (48). Intratubular pressures did not differ among nondilated and cystic nephrons in the treated rats and nephrons in control animals, but microperfusion of the cystic nephrons caused pressure to rise significantly higher than it did in the others. The excretion of [3H]inulin after microinjection into cystic nephrons was reduced and delayed compared with that in nondilated tubules. Similar findings were obtained in rats in which cystic changes were produced by diphenylamine and diphenylthiazole (49). Tanner et al. (162) repeated these experiments in the Han:SPRD rat. The kidneys in the examined cystic rats were twice the size of those in normal control animals, but mean arterial pressure, GFR, and urine flow rate did not differ in the two groups. Pressures in the cystic nephrons were modestly elevated above that registered in the nephrons of the control rats, 18.5 versus 14.3 mmHg. Pressures in the noncystic tubules of the cystic rats did not differ statistically from those in the cysts or in the normal rats. The response to microinfusion into the cysts at 15 and 50 nl/min was highly variable. Thirty-nine percent of the cysts displayed a pressure increase above 30 mmHg and were considered to be obstructed. In the remaining 61%, the pressure increase was much less and similar to that obtained in control animals. When lissamine green was injected intravenously, the dye appeared in all the observed surface cysts, and washout of the dye occurred, albeit at a delayed rate, indicating that these cysts were connected to functioning tubules. Scanning electron microscopy studies of these cystic kidneys did find evidence of obstruction in some cysts in the form of tubular casts or narrowing of the tubular lumen. Polyps were not observed. These results suggest that in this genetic model, as compared with the chemical models, tubular obstruction may contribute to cyst formation but is not a necessary component (162). Similar conclusions were reached in studies of two genetic mouse models (62, 160). These models differ from the human form of ADPKD in which the majority of cysts do not retain a tubular connection (70). A more direct assessment of basement membrane deformability was made by applying a negative pressure to a tubular or cystic wall via a micropipette and measuring the distance the wall was pulled into the pipette (69). Viscoelastic creep was determined by measuring the time-dependent effect of pipette aspiration on membrane deformation. Four models of cystic disease were studied: a mouse genetic model of recessive polycystic kidney disease [C57 BL/6J (cpp/cpk)], two chemically induced models (rats fed either diphenylthiazole or nordihydroguaiaretic acid), and an environmental model (the CFWw mouse develops cystic disease when raised in a conventional environment rather than in a germ-free environment). No differences appeared in the measurements of deformability and viscoelastic creep between normal and cystic tubules in any of the animal models. The calculated transtubular pressure that would be required to dilate the tubules to the extent seen in these rodent models was much higher than the intratubular pressures that have been measured. Thus tubular obstruction and a reduction in the tensile strength of the basement membrane are not constant features of cystic disease. However, cellular proliferation occurs in all the animal models and in the human. Every cyst that has been examined has shown signs of proliferation, including those cysts that did not exhibit polyps or cordlike hyperplasia. It seems apparent that this proliferation, with each cell making its contribution to the basement membrane, is the factor that initiates cyst formation. Studies of this proliferation have concentrated on the cultured cell models. B. Cyst Formation by Cultured Cells
The microcyst model pioneered by McAteer et al. (118) has proven to be very useful in studies of growth of cysts by renal epithelial cells. Madin-Darby canine kidney cells seeded within a collagen matrix form cysts by clonal growth of individual cells. These microcysts are filled with fluid, and the cells in the lining monolayer are polarized so that the apical surface faces the lumen and the basolateral surface is in contact with the collagen matrix. (These cysts formed by cultured cells are referred to as microcysts to distinguish them from the cysts formed in vivo in the polycystic kidney.) The only source for the fluid is secretion across the cyst wall. Hydrostatic pressure within the microcyst was found to exceed that in the bath by an average of 6.7 mmH2O; thus the secretion must involve the addition of solute to the cyst cavity (73). Cell proliferation in MDCK monolayers can be stimulated by stretching the underlying membrane support (166). However, secretion of fluid into the microcysts (presumably stretching the cyst wall) is not necessary for cell proliferation. Ouabain stopped fluid secretion by the MDCK microcysts, but the cells continued to proliferate and a solid tumorlike structure was formed (73). Prostaglandin E1, which stimulates cAMP production in MDCK cells (167), increased the growth of fluid-filled microcysts in defined medium, suggesting that cAMP may play a role both in cell proliferation and in fluid secretion (73). In a more detailed study (112), it was found that arginine vasopressin (AVP), cholera toxin, and forskolin increased the number and volume of MDCK microcysts and the proliferation of cells in monolayer cultures. Prostaglandin E1, cholera toxin, and forskolin also increased the level of cAMP in the microcysts, and 8-bromo-cAMP increased the number and volume of microcysts and the proliferation of cells in monolayer cultures. The rate of fluid secretion by the monolayers was measured and found to be stimulated by forskolin, PGE1, and 8-bromo-cAMP. The effects of these agonists on microcyst formation and fluid secretion were potentiated by 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterase. By itself, IBMX also stimulated cell proliferation but did not induce cyst formation. Levels of cAMP generated in response to IBMX were lower than those obtained in response to forskolin, PGE1, and cholera toxin, but IBMX was as potent as the other agents in generating cell proliferation. This suggests that relatively low levels of cAMP are sufficient to maximally stimulate proliferation but that higher levels are required to induce fluid secretion. Both proliferation and fluid secretion are required to induce microcyst formation by MDCK cells (112). The ability of primary cultures of cortical cells removed from normal human kidneys (HKC) to form microcysts was examined (111, 123, 125). Histochemical analysis indicated that microcysts and monolayers were formed primarily by cells derived from the distal nephron (123). The polarity of these cells was the same as that of cells in the MDCK microcysts; the apical membrane faced the lumen of the cyst. In contrast to MDCK cells, agents that increase cAMP levels within cells did not stimulate microcyst formation and growth in the absence of epidermal growth factor (EGF) or transforming growth factor ( TGF ) - End-stage ADPKD kidneys removed from patients for medical reasons have been the major source of tissue for developing primary cultures. These cultures have been derived from explants of cyst walls (185) or from cells that were freed from minced cyst walls by use of collagenase (111). McAteer et al. (117) found that when a section of cyst wall was embedded in and covered with collagen, the proliferating cells commonly formed an epithelial sac in which fluid accumulated. Cells seeded within a collagen matrix also formed cysts by clonal growth (111). As with the HKC cultures, EGF was required for the initiation of microcyst formation, but, unlike the HKC cultures, EGF alone was not sufficient. Agonists that induce the production of cAMP were also required. These agonists also induced fluid secretion by monolayers of the ADPKD cells as they did in monolayers of the MDCK and HKC cells (67, 111). The studies described above make it clear that cAMP is involved in the proliferation of the cultured cells and in generating fluid secretion. The roles of additional factors potentially involved in cystic cell proliferation, including endocrine, paracrine, and autocrine substances, and oncogenes have been studied (for reviews, see Refs. 33, 183). They are not reviewed here. The studies performed with the MDCK and HKC cells also indicate that abnormalities in the PKD1 or PKD2 gene are not required to induce cyst formation or fluid secretion by renal epithelial cells. A. Madin-Darby Canine Kidney Cell Model
Mangoo-Karim et al. (112) analyzed the composition of the fluid secreted by MDCK microcysts and monolayers using electron-probe analysis. The ratio of Cl In the standard model for Cl A variety of studies have focused on the Cl Tanner and co-workers (164, 165) developed a novel technique to investigate the role of these Cl Madin-Darby canine kidney microcysts superfused with control media absorbed fluid from the cyst cavity at a slow rate (158, 164). Microcysts superfused with dibutyryl cAMP, forskolin, or AVP, often in conjunction with IBMX, secreted fluid at a constant rate for 60-90 min. Cell volume fell upon initiation of secretion and did not recover within 60 min (158, 164). Ouabain (0.1 mM), applied to the basolateral surface of the microcysts, inhibited fluid secretion induced by the secretagogues. The direction of the Isc and the magnitude of the increase induced by the application of forskolin to the monolayers indicated that fluid secretion is probably driven by active anion transport from the basolateral to the apical surface (75). The cAMP content of the monolayers was also increased by forskolin. Microelectrode measurements conducted on the unstimulated microcyst by Macias et al. (108) indicated that the transepithelial electrochemical gradient across the cyst wall opposed passive Cl Tanner et al. (164) investigated the nature of the mechanism transporting Cl The microcyst cell volume fell ~7% whenever secretion was initiated by AVP or forskolin, indicating a loss of cell solute (158, 164). Apparently, activation of the cotransporter limited that loss, since a further loss of cell volume occurred after the application of 0.1 mM bumetanide (158). Epifluorescent measurements of changes in cell electrical potential indicated that application of 0.1 mM bumetanide, after initiation of secretion, hyperpolarized the cell. This may have been the result of a fall in the depolarizing efflux of Cl The role of electrical gradients in Cl
These studies strongly support the conclusion that Cl
B. Autosomal Dominant Polycystic Kidney Disease Tissue
Perrone and co-workers (133, 136) were the first to attempt to investigate the transport mechanisms present in ADPKD tissue by mounting segments of cyst walls in Ussing chambers. The cysts from which the segments were dissected were classified as gradient or nongradient cysts on the basis of Na+ and K+ concentrations in the cyst fluid. The cyst epithelium removed from nongradient cysts exhibited a high conductance (20-80 mS/cm2) and quite low Vt and Isc values. Amiloride, ouabain, acetazolamide, and bumetanide did not affect these values or the unidirectional fluxes of Na+ and Cl Ye and Grantham (190) applied a gravimetric method to directly demonstrate the ability of the cystic epithelium to secrete fluid in vitro. Intact cysts were carefully dissected from ADPKD kidneys. Cyst fluid was aspirated to determine its volume so that cyst surface area could be calculated. One-third of the volume of cyst fluid was reinjected into the cavity of some cysts; culture medium was injected into the cavity of the remaining cysts. All the cysts were then incubated in the culture medium. The net rate of fluid transport was determined by weighing the cysts at 24-h intervals. Forskolin was added to the bathing medium after the control period. Cysts containing natural cyst fluid secreted fluid at a rate of 0.87 µl·cm In a more detailed study of intact cysts, 30 were dissected from the kidneys of 2 different donors (75). The cysts were filled with culture medium and incubated in the same medium. Forskolin (10 µM) was added to the bath of 10 cysts. All the cysts secreted fluid during the 24-h period at a mean rate of 0.19 ± 0.04 µl·cm Monolayers of cultured ADPKD cells were also successfully studied in Ussing chambers (75, 113). In 36 such preparations derived from cysts removed from 7 kidneys, the Rt averaged 156
Several approaches were taken to determine if the anion secreted by ADPKD tissue is Cl Experiments performed on microcysts formed by cultured ADPKD cells also verified that the anion secreted is Cl
The efflux pathway for Cl
A third study of CFTR in cystic tissue provided additional indications that Cl Exact identification of the basolateral Cl In 1991, before the work on ADPKD tissue described above, Wilson et al. (186) proposed that Na+ is the ion that is actively secreted by polycystic tissue. They had investigated the activity and cellular location of Na+-K+-ATPase in slices of normal and early-stage ADPKD kidneys using immunocytochemical and enzyme cytochemical techniques. They found that the activity of the enzyme in homogenates of cystic tissue from early-stage kidneys was three times higher than that in normal tissue. Using polyclonal antibodies raised against the A variety of histological and functional studies could not confirm the results of Wilson et al. (186). Carone et al. (25) examined the location of Na+-K+-ATPase in ADPKD kidneys snap-frozen less than 5 min after removal from patients. Using a polyclonal antibody to the Several of the animal models of polycystic kidney disease have also been examined for mislocation of Na+-K+-ATPase (4, 9, 26, 97, 127, 129, 146, 161). None of the studies found the enzyme to be exclusively located in the apical membrane. It was reported to be exclusively located in the basolateral membranes of cystic tissue in the Hans:SPRD rat model (146) and in two of the genetic mice models (97, 161). Both apical and basolateral localization was reported in the cpk mouse model (4, 129), in the pcy mouse, in the diphenylthiazole-induced rat model, and in the glucocorticoid-induced mouse model (129). Focal loss of the enzyme from the basolateral membrane and localization in the cytoplasm were reported in one chemically induced rat model (26). Thus there is no corroborative evidence that Na+-K+-ATPase is mislocated to the apical membrane of cystic cells in ADPKD or that Na+ secretion drives fluid secretion by these cells. The weight of the evidence indicates that Cl
As the data in Table 2 indicate, both monolayers and microcysts, composed of ADPKD cells, absorbed fluid in the absence of secretagogues. Net fluid absorption was not observed in the intact cyst preparation in the absence of applied secretagogues, but that may be due to the possible presence of an endogenous secretagogue (vide infra) that had accumulated in the cells before the cysts were removed from their native environment (190). It is possible that separate cell populations are responsible for the ability of the monolayers to both absorb and secrete fluid. That possibility is diminished in the microcysts that were grown by seeding a small number of cells within a collagen matrix. Most of the microcysts develop by clonal growth from single cells. It seems apparent that the cells are capable of directing fluid transport in either direction, an ability that has been demonstrated in tracheal and intestinal epithelia (3, 76). The transport mechanisms that are responsible for absorption by ADPKD tissue remain elusive. Perrone (133) has reported that the Vt and Isc, generated by walls of two gradient cysts mounted in Ussing chambers, were reduced by amiloride at a concentration, 10 µM, known to inhibit Na+ channels. Wilson et al. (186) reported that amiloride (100 µM) inhibited the apical to basal flux of 22Na+ and suggested that a Na+/H+ exchanger was generating the flux. We have been unable to reduce Isc in ADPKD monolayers by 1 mM amiloride, by hydrochlorothiazide, or by inhibition of carbonic anhydrase with acetazolamide (unpublished data). As described in section VIA, 26-33% of the kidney cysts contain fluid with low Na+ and Cl It is possible that the gradient cysts represent the minority of cysts that were found to retain a tubular connection. These cysts, originating from distal tubules and collecting ducts, may fill slowly with filtrate whose composition has been modified by upstream tubular segments. The accumulation of impermeant organic solutes may impede fluid absorption. During the life of the cyst, periods of salt absorption may alternate with periods of secretion as the level of secretagogues to which the cyst is exposed varies with time. When secretion predominates, it may actually be accelerated by the transepithelial Cl Cysts frequently appear in the intrahepatic biliary tree in ADPKD. Their occurrence is more common in women, and the risk is increased by pregnancy and exposure to female sex steroids (57). The histology of the biliary cysts has not been as extensively studied as that of the renal cysts, but there are many similarities. Segmental irregular dilatations of the bile ducts have been noted. Cysts larger than 0.5 cm in diameter did not communicate with the biliary tree, but the appearance of the ducts in the immediate vicinity of the cysts suggested that the cysts may compress the ducts from which they originated (80). There is evidence of flat or polyploid hyperplasia (142). In addition, numerous areas of a labyrinthine collection of dilated, tortuous, interanastamosing small ducts appear. They evidently are attached to the main duct by sparse connecting ducts. These have been called variously, von Meyenburg complexes (80) or biliary microhamartomas (142). The fluid secreted by the normal ductal epithelium has an electrolyte composition that is similar to plasma (176). Secretin increases cAMP levels in duct cells and stimulates secretion of a fluid that is rich in bicarbonate (105, 176). Cystic fibrosis transmembrane conductance regulator was found at or near the apical surface of bile duct cells (31), and the use of monoclonal antibodies to the human Cl Immortalized cell lines have been derived from epithelial cells lining normal human intrahepatic bile ductules (IBE cells) and from the cells lining ADPKD hepatic cysts (LCDE cells) (81, 135). Studies of the regulation of intracellular pH by IBE cells indicated the probable presence of a Na+/H+ exchanger, a Na+-dependent Cl Extensive evidence gathered from studies of ADPKD renal tissue and cultured preparations, reviewed above, indicates that the growth of renal cysts involves a coordination of the processes of cellular proliferation and fluid secretion. The cAMP signaling pathway has been shown to be involved in both processes (40, 67, 75, 84, 111, 113, 178, 190). The agonists include permeable forms of cAMP (67, 75, 178), phosphodiesterase inhibitors (67), forskolin (40, 67, 75, 84, 111, 113, 178, 190), and factors that act by receptor-mediated stimulation, such as PGE1 (67), vasoactive intestinal polypeptide, and secretin (unpublished data). Thus a variety of circulating factors, normally present in the blood, or a number of paracrine or autocrine factors could trigger the cAMP signaling pathway to stimulate cyst growth and fluid secretion in vivo. Ye et al. (189) hypothesized that traces of modulators of the cAMP signaling pathway might collect in cyst fluid. Accordingly, they examined the ability of fluid collected from human ADPKD cysts to stimulate microcyst formation by HKC and MDCK cells and fluid secretion by monolayers of these cells in vitro. The effect of serum and urine samples was also tested. Cyst fluid added to the medium (final concentration 1-20%) caused MDCK and HKC cells, cultured in collagen matrix, to form microcysts in culture and stimulated fluid secretion by monolayers of these cells. The rates of fluid secretion generated by the MDCK monolayers correlated directly with the rates of fluid secretion by the HKC monolayers and with the extent of microcyst formation in collagen matrices by both types of cells. The secretory activity of the urine was negligible, but it was present in low levels in the serum of normal and ADPKD subjects. In a study of intact cysts, dissected from ADPKD kidneys and incubated in vitro, secretion was maintained when the native cyst fluid was left in the cyst but was insignificant when the fluid was replaced with culture medium (190). A chloroform-methanol extract equivalent to a 10% concentration of cyst fluid increased cAMP content of MDCK monolayers sixfold (74). This effect was enhanced by the presence of IBMX. Further investigation revealed that the active substance present in cyst fluid is a lipophilic substance of molecular mass <3,500 Da that is not destroyed by freezing, boiling, or proteolytic digestion. It resists alkaline hydrolysis, excluding contribution of ester groups, but activity is destroyed by borohydride which reduces ketone groups, by periodate which interrupts vicinal hydroxyl groups, and by hydrolysis in HCl (72). Chromatography indicated that the secretagogue was present in a fraction of neutral lipids enriched in monoglycerides (74). Arachidonic acid was present in some of the chromatography fractions. However, the effect of arachidonic acid on fluid secretion by MDCK cells was blocked by indomethacin, whereas the inhibitor did not alter the effect of the secretagogue on fluid secretion. Thin-layer chromatography and HPLC indicated that the lipid is less polar than sphingosine and more polar than triolein (72). Interstitial inflammation and fibrosis are a common feature of the end-stage kidney in ADPKD. The recent discovery of an unusual nonpolar inflammatory and chemotactic lipid in the urine of rats with acquired proteinuria and tubulointerstitial nephritis (98) raised the possibility that the lipids in ADPKD cyst fluid and nephrotic urine might be chemically and functionally related. Thin-layer chromatography and HPLC fractions of ADPKD cyst fluid were bioassayed for both secretagogue and monocyte chemotactic activity. The latter was determined by measuring the transmembrane migration of murine RAW 264.7 cells. Both activities resided in the same chromatography fraction (72). A chemotactic lipid with chemical properties similar to the cyst fluid secretagogue has been identified in the conditioned medium of proximal tubules incubated with an albumin-oleate complex (98). An HPLC-purified extract of this tubule conditioned medium stimulated fluid secretion and monocyte chemotaxis. The medium obtained from incubation of tubules with either albumin or oleate had no effect (72). Schreiner and co-workers (98, 149) have suggested that tubular cells may generate inflammatory lipids from albumin-fatty acid complexes that are filtered in excess in a variety of renal diseases. The proximal tubule epithelium endocytoses the complex, catabolizes the albumin into its constituent amino acids, and metabolizes the fatty acids into a variety of polar and neutral lipids. At least one of the neutral lipids, resembling a monoglyceride, is a potent chemoattractant for monocytes and macrophages. This inflammatory lipid and the secretagogue may be the same or closely allied lipids. In ADPKD, the majority of cysts are not connected to the glomeruli; however, nongradient cysts do contain significant protein that may be complexed with fatty acids (15, 61). In addition, fatty acids are known to gain access to cells via the organic acid secretory pathway (8, 157, 171, 173). Products of their metabolism may be released into the cyst cavities and into the surrounding interstitium. Observations of mice with polycystic kidney disease support the hypothesis that inflammatory and secretory lipids are generated in this disease. A lipid found in the cyst fluid in DBA/2FG pcy-pcy mice stimulated cAMP production, fluid secretion, and proliferation by MDCK cells (188). It also promoted increased migration of murine monocytes in vitro (J. J. Grantham, G. F. Schreiner, and A. Joly, unpublished data). In addition, the course of the murine disease was improved by treatment with methylprednisolone, which strikingly diminishes the interstitial inflammatory infiltrate (63). The results of these studies have led to the conclusion that human cyst fluids harbor potent secretagogue and chemotactic lipids that may play an important role in determining the functional course of ADPKD. These lipids may have similar structure and may be produced by renal epithelial cells (72). Because the lipid or lipids in cyst fluid promote proliferation of cells, secretion of fluid, and chemotaxis, we have named the substance(s) cyst activating factor. A variety of questions relating to epithelial transport in polycystic kidney disease remain. For obvious reasons, the focus of research has been on the function of the cystic epithelium. However, studies of the function of the intact ADPKD kidney, before the onset of the early stages of renal failure, disclose subtle changes in function (see sect. V). Are these changes the direct consequence of altered function by cystic cells, the consequence of disruption in the organization of the tubular and vascular components of the medulla, or are they due to unrecognized abnormalities in normal-appearing tubular segments? To state it differently, all the renal epithelial cells presumably contain a mutated PKD gene. Is there a functional or structural consequence to the partial loss of gene product? There are two major questions regarding fluid transport by the cyst that may be related. As described in section IX, net fluid absorption is routinely measured in cultured ADPKD monolayers and microcysts in the absence of secretagogues. The transport mechanism driving this absorption has not been satisfactorily described. In addition, the mechanisms for fluid accumulation in the gradient cysts (sect. X) that maintain low concentrations of Na+ and Cl With regard to Cl The finding of a reduction in the activity of the Na+-independent Cl A. Renal Epithelial Cells
The transport properties of ADPKD cells do not appear to differ importantly from those of some epithelial cells that are normally present in the normal nephron and in the collecting tubule. Sodium chloride secretion has been shown to occur in vivo in the rat distal tubule (148) and in the medullary collecting duct in response to volume loading (154, 156). It has also been noted to occur in vitro in isolated and perfused rat inner medullary collecting ducts (IMCD) in response to agonists of the cAMP signaling pathway such as AVP (89, 145, 177, 187). Several primary and immortalized cell lines will also secrete Cl The mRNA for CFTR has been detected in all nephron segments. The CFTR protein is diffusely dispersed through the cells of the proximal tubule and thin limb of Henle's loop and is localized to the apical membrane region of the distal tubule, the principal cells of the cortical collecting duct, and the cells of the IMCD. Patch-clamp analysis has indicated that Cl Chloride entry mechanisms in the basolateral membrane may include the BSC2 or NKCC1 form of the Na+-K+-2Cl B. Intestinal Crypt and Lung Cells
The transport properties of intestinal crypt cells change as they migrate from the base of the crypt to the surface. The developing colonocytes at the base secrete Cl A somewhat similar pattern is observed in the development of lung epithelial cells. Experiments conducted in vivo have demonstrated that the lung epithelium secretes Cl Does a similar pattern occur in the development of renal epithelial cells? Mangoo-Karim et al. (110) suspended straight proximal tubule and cortical collecting duct segments from the rabbit within a collagen matrix and exposed them to a defined medium. Initially, the segments displayed no lumen, but in the presence of IBMX and cholera toxin or 8-bromo-cAMP, a lumen gradually developed and grew in size over a period of days. As noted above, cells derived from the cortex of the normal human kidney will, like ADPKD and MDCK cells, form microcysts in culture and will secrete fluid in the presence of cAMP agonists (Table 2). Thus, in three different organs, the lung, the intestine, and the kidney, there are examples of immature epithelial cells that secrete Cl The genetic defect in ADPKD causes a cell or a small group of cells to begin to proliferate at a slow rate at discrete locations from the glomerulus to the collecting tubule in a small fraction of the nephron population. As these relatively undifferentiated epithelial cells proliferate, they balloon the lumen into a cyst that, as it grows, is likely to pinch off from the parent nephron. As the cyst expands, it impinges on neighboring nephrons and restructures the interstitial matrix. The defects in renal function that occur before the onset of renal failure are subtle in nature. A major factor involved in causing these mild abnormalities in function may be the disruption of the medullary architecture by the growing cysts. As the cysts continue to grow and to alter the renal parenchyma, the number of functioning nephrons apparently falls, and full renal failure develops in a large segment of the patient population. The possibility that the genetic defect in ADPKD may alter the function of tubules or tubular segments that do not exhibit developing cysts has not been intensively investigated. The morphology of the cells found in various cysts differs, but the large majority of cysts are composed of poorly differentiated cells that do not resemble any cell type found in the nephron. The proliferation of the cystic cells is stimulated by factors that increase intracellular cAMP levels. These same factors induce the cells to secrete fluid, and it is this active secretion that is responsible for the accumulation of fluid in the majority of cysts. A lipid factor that accumulates in cyst fluid was found to be a cAMP agonist that induces both proliferation and fluid secretion. It may be a major factor that stimulates cyst growth. Active secretion of Cl Cultured cells derived from the normal human renal cortex and MDCK cells will also form cysts and secrete fluid. The developing cells at the base of the intestinal crypt and fetal lung epithelial cells also secrete Cl
I. INTRODUCTION
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II. GENETIC FACTORS
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III. MORPHOLOGY
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FIG. 1.
A: scanning electron microscopy of a hemisection of a cyst found in a kidney from a patient with autosomal dominant polycystic kidney disease. Surrounding tubular structures appear to be compressed by cyst. B: a higher magnification of inner surface of cyst. Cyst is lined with a flattened, simple, poorly differentiated epithelial cell layer.
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TABLE 1.
Morphological characteristics of autosomal dominant polycystic kidney disease cysts
IV. ANIMAL AND CELL MODELS
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-globin promoter (64). Cysts can also be chemically induced in vivo by administration of the antioxidants nordihydroguaiaretic acid, diphenylamine, and diphenylthiazole. Glucocorticoids will induce cysts in newborn animals (33, 64, 119). An in vitro organ culture model has been developed (5, 119). Mouse kidneys removed from the fetus at 2 wk survive for extended periods and progress through certain stages of nephrogenesis. The addition of corticosteroids or thyroxine to the organ culture medium reversibly promotes the development of cysts.
V. ABNORMALITIES IN FUNCTION IN THE POLYCYSTIC KIDNEY
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VI. CYST FLUID
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concentrations, whereas the concentrations of these substances in nongradient cysts fall approximately into the range usually seen in plasma. Generally, approximately two-thirds of the total population of the cysts sampled fall into the nongradient category and 26-33% fall into the gradient category, depending on the authors' definition of the two categories (60, 88). Huseman et al. (88) noted that the proportion of the two types of cysts approximated that of the population of the proximal and distal tubules found on the surface of the normal kidney. Nongradient cysts have been observed in all kidneys studied, whereas gradient cysts have not been identified in every case. Gardner et al. (60) have contended that adult polycystic kidneys differ from each other because of this. A statistical analysis applied to the available data indicated that it is unlikely that a sampling error contributed to this discrepancy. However, in those kidneys in which gradient cysts were not found, only 5-12 cysts were sampled per kidney out of a population that probably exceeds 1,000. concentrations of fluid from gradient cysts imply that other solutes contribute significantly to the total solute concentration, and Gardner (59) found that amino acids accounted for 50-100 mosmol/kgH2O. More remarkable is the finding that the glucose concentration of proximal or nongradient cysts is similar to that of serum; the concentration in distal or gradient cysts is higher (59, 61, 88). This finding implies that the proximal cysts do not reabsorb glucose or that the cyst walls are quite permeant to it. The latter may be quite probable.
VII. CYST GROWTH
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(111, 123). Either of these growth factors was sufficient to promote microcyst initiation and growth. Their effect was strongly augmented by inclusion of insulin in the growth medium. Platelet-derived growth factor, TGF-, and basic fibroblast growth factor did not initiate microcyst formation; in fact, TGF- inhibited the effect of EGF. Receptor-mediated agonists of the cAMP pathway, PGE1, AVP, parathyroid hormone, vasoactive intestinal polypeptide, and isoproterenol enhanced the initiation and enlargement of the microcysts when EGF and insulin were present in the growth medium. Forskolin, cholera toxin, IBMX, and 8-bromo-cAMP were also effective, as was a relatively high concentration (107 M) of ANF, which increases intracellular levels of cGMP. In contrast to their effect on microcyst formation and growth, forskolin, PGE1, AVP, and 8-bromo-cAMP induced fluid secretion by monolayers of cells in the absence of EGF. Epidermal growth factor itself did not induce fluid secretion; however, it potentiated fluid secretion in the presence of forskolin (111, 123, 125).
VIII. TRANSPORT MECHANISMS INVOLVED IN FLUID SECRETION
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concentrations of the secreted fluid to that of the bathing medium was 1.12 for the microcysts and 1.18 for the monolayers. The corresponding Na+ concentration ratios were 0.98 and 1.02. These values suggested that Cl is secreted by MDCK cells. Secretion of Cl is known to drive fluid secretion by a variety of epithelia, and Simmons and co-workers (22, 152, 153) had reported that monolayers of MDCK cells grown on a permeable membrane secreted Cl in response to forskolin, vasopressin, PGE1, and vasoactive intestinal polypeptide. secretion, Na+-K+-ATPase, located in the basolateral membrane and acting in concert with K+ channels, establishes the requisite chemical and electrical gradients that are utilized by the Cl transporters (106). The Na+-K+-2Cl cotransporter, also located in the basolateral membrane, brings Cl into the cell. A Cl channel in the apical membrane provides the efflux pathway. Secretagogues, often acting through the cAMP signal transduction system, activate the Cl channel. The cotransporter and K+ conductance pathways in the basolateral membrane may also be activated by initiation of secretion. The activation of Cl channels in the apical membrane and increased efflux of K+ across the basolateral membrane establishes a transepithelial electrical gradient, lumen negative, that drives net Na+ diffusion through the paracellular pathway. The addition of NaCl to the luminal fluid provides the osmotic force to drive fluid secretion. transport mechanisms in MDCK cells (see Ref. 153 for review). The presence of a large-conductance Cl channel in MDCK cells, activated by epinephrine, was reported by Kolb et al. (102). Agents that raise cellular cAMP levels increased a Cl conductance that is blocked by 9-anthracene carboxylate and diphenylamine-2-carboxylate (DPC) (18, 104) and the Cl channel blocker 5-nitro-2-(3-phenylpropyl-amino)benzoic acid inhibited Cl secretion (152). Bumetanide, an inhibitor of Na+-K+-2Cl cotransport, reduced cell Cl accumulation (151). Measurements of [3H]bumetanide binding to monolayers located the cotransporter on the basolateral surface and indicated that the density of the cotransporters was similar to that of the Na+-K+-ATPase mechanism (21). transport mechanisms in fluid secretion by MDCK microcysts. A small section of collagen gel containing the cysts was placed in a perfusion chamber on the stage of an inverted microscope and superfused with culture medium or with Ringer solution. A single microcyst was selected for examination, and net fluid transport by the epithelium was measured by following changes in cyst cavity volume. This volume was determined by morphometric measurement of the diameter of the cyst cavity in videotaped images of the equatorial plane of the cyst. The volume of the cells lining the microcyst was calculated by subtraction of the cyst cavity volume from the total cyst volume. This technique was modified by Sullivan et al. (158) to permit epifluorescent measurements in single microcysts of cell pH with the use of 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein and cell potential changes with the use of bis-oxonol (158). Macias et al. (108) used double-barreled microelectrodes to measure electrical gradients and Cl activity in the cells and in the cyst cavity. The subtype of MDCK cells used in the microcyst experiments was also cultured to form monolayers of cells on permeable membranes. Fluid secretion by these monolayers was measured in 24-h periods, and monolayers were also mounted in Ussing chambers to permit measurements of transepithelial voltage (Vt), resistance (Rt), and short-circuit current (Isc) (75, 113). secretion. The cellular Cl activity, 60 ± 1 mM, exceeded the value that would exist if electrochemical equilibrium for Cl prevailed across the basolateral and apical membranes. Thus Cl entry into the cell across the basolateral membrane must occur against an electrochemical gradient, whereas exit across the apical membrane could occur passively in response to the favorable electrochemical gradient. The results of the microelectrode study suggested that a Cl conductance pathway may be present in the apical membrane. This hypothesis was supported by the results of experiments in which the anion channel blocker DPC was applied to the apical surface of monolayers (113). At 3 mM, DPC inhibited fluid secretion initiated by application of forskolin. It also depolarized the monolayers and inhibited Isc, confirming the results of earlier studies (18, 104, 152). into the cell across the basolateral membrane with the use of Cl transport inhibitors applied to microcysts stimulated to secrete fluid by AVP plus IBMX. Secretion rates were measured in separate control and experimental groups. Furosemide (0.1 mM) inhibited secretion, but bumetanide (0.01 mM) caused an insignificant decrease of 23%, and chlorothiazide (1 mM) had no effect. The nominal absence of bicarbonate and CO2 inhibited secretion, and pretreatment with DIDS (0.1 mM) inhibited secretion as did amiloride (1 mM). However, acetazolamide (0.1 mM) did not. Also, DIDS inhibited the loss of cell volume when the cyst was exposed to a solution containing no Cl. Microelectrode measurements on cysts not exposed to secretagogues indicated that the cell Cl level fell when the microcyst was exposed to a high HCO3 medium and when 1 mM amiloride was added to the medium (108). The results of these studies suggested that a Cl/HCO3 exchanger, paired with a Na+/H+ exchanger, operated in the basolateral membrane. The authors proposed that the Cl/HCO3 exchanger is responsible for Cl entry across the basolateral membrane when secretion is stimulated (108, 164). However, the results of similar experiments did not support these conclusions (158). In this study, control and experimental measurements were made sequentially in 30-min periods on each microcyst. Secretion initiated by AVP plus IBMX was not affected by subsequent addition of DIDS (0.1 mM) to the bathing medium. Cell pH might be expected to change if initiation of secretion accelerated Cl/HCO3 exchange. However, epifluorescent measurements of cell pH indicated that no transient or long-lasting change in cell pH occurred. The application of bumetanide (0.1 mM) did not alter the slow rate of fluid reabsorption or cell volume when it was added to the bathing medium in the absence of a secretagogue. However, 0.01 mM bumetanide reduced the rate of secretion to values not different from zero after the administration of AVP plus IBMX, an effect that was partly reversed by the removal of the inhibitor. It was concluded that Cl enters the cell during secretion via a Na+-Cl or a Na+-K+-2Cl cotransporter. The Cl/HCO3 exchanger may maintain the high Cl concentration within the resting cell, but activation of the cotransporter maintains the supply of Cl to the cell during secretion (158). Studies conducted in other secretory epithelia are consistent with this interpretation. The binding of benzmetanide, a potent inhibitor of the cotransporter, to cell membranes of the shark rectal gland is greatly increased by the activation of secretion (53, 107). The binding of bumetanide to cultured canine airway epithelia is also enhanced by activation of secretion (83). across the apical membrane resulting from inhibition of Cl entry into the cell via the electrically neutral cotransporter. Bumetanide also reduced forskolin-stimulated fluid secretion and Isc in monolayers of the ADPKD cells (113). and fluid secretion was investigated in experiments on MDCK microcysts in which Ba2+ (1 mM) was added subsequent to the initiation of secretion by AVP plus IBMX (158). Barium depolarized the cell, blocked fluid secretion, and caused an increase in cell volume (Fig. 2). These changes were completely reversed by removal of Ba2+. It was considered that the depolarization of the cell resulted from blockade of K+ channels in the basolateral membrane. The depolarization evidently reduced the electrochemical force driving Cl efflux across the apical membrane, resulting in the inhibition of fluid secretion. The retention of K+ and Cl within the cell may have caused the expansion of cell volume that was observed. It had been demonstrated earlier that Ba2+-induced depolarization of the basolateral membrane also inhibited Cl secretion by the canine tracheal epithelium (181). Greger and Schlatter (77) found that depolarization of the basolateral membrane by Ba2+ reduced the electrochemical gradient for Cl efflux from the cells of the shark rectal gland.
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FIG. 2.
Effect of barium on a cultured Madin-Darby canine kidney cell microcyst induced to secrete fluid by superfusion with arginine vasopressin (AVP) and 3-isobutyl-1-methylxanthine (IBMX). Cavity volume and volume of cell layer were determined by morphometric measurement of a videotaped image of cyst with microscope focused on equatorial plane of cyst (see Fig. 3A). Changes in membrane electrical potential were determined by epifluorimetric measurement of cellular bis-oxonol levels. Top: cavity volume. Solid lines are regression lines for each period and were used to calculate fluid transport rates. Before application of secretagogues, volume was stable. Superfusion of cyst with a medium containing 10 mU/ml AVP and 0.1 mM IBMX initiated fluid secretion at a rate of 7.2 nl·min 1·cm2 cavity surface area1. Addition of 1 mM barium to superfusion medium reversed fluid secretion to absorption at a rate of 
3.37 nl·min1·cm2. After removal of barium, secretion resumed at a rate of 5.45 nl·min1·cm2. Middle: experimental-to-control ratio (E/C) of cell volume. Horizontal dashed line indicates an E/C value of 1.00. Control cell volume was 1.10 µl/cm2 cyst outer surface area. Upon initiation of secretion, cell volume fell rapidly to ~91% of control level. After addition of barium, volume transiently rose to 95% of control level. Bottom: E/C of epifluorescence of bis-oxonol. A fall in ratio indicates membrane hyperpolarization; a rise indicates depolarization. Addition of secretagogues caused membrane hyperpolarization, and subsequent exposure to barium caused membranes to depolarize. [From Sullivan et al. (158). Used with permission from Kidney International.]
is secreted by MDCK cells by mechanisms that are very similar to those employed by a variety of secretory epithelia. In addition, the data indicate that fluid secretion by monolayers and microcysts formed by these cells is driven by the active transport of Cl. Monolayers and microcysts derived from primary cultures of human kidney cortex cells also secreted fluid in response to adenylyl cyclase agonists (Table 2).
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TABLE 2.
Fluid transport rates in preparations of cyst-forming epithelia
. The conductances of two gradient cysts were lower, 3.1 and 6.5 mS/cm2, Vt and Isc were higher, and the unidirectional fluxes of Na+ and Cl were lower than in the nongradient cysts. Amiloride inhibited the Isc in the gradient cysts. The effects of agents that increase cellular cAMP levels were not investigated in these early studies. Another attempt to mount segments of cyst walls in Ussing chambers was unsuccessful (unpublished data). The cyst walls were fibrous, and the thickness of the tissue was highly irregular. An inability to obtain a tight electrical seal of the chamber wall to the tissue may have caused the low and highly variable Rt and Vt values measured. However, the cyst walls are active as another method has documented (190).2·h1. The addition of forskolin did not significantly alter that rate. The cysts containing culture fluid did not secrete fluid at a significant rate until forskolin was added to the bathing medium (Table 2). The rate of fluid secretion by cysts containing cyst fluid and bathed in medium containing forskolin was inhibited by ouabain (0.01 or 0.1 mM) added to the bath. This study indicated that the cystic epithelium secretes fluid by an active process and that secretion can be increased by an unidentified secretagogue present in cyst fluid. Monolayers developed from primary cultures of ADPKD cells also secreted fluid when agonists that raise the levels of cellular cAMP were applied (75, 111, 113, 124), as did the microcysts developed in culture (178) (Table 2). In fact, the cultured cells in both the monolayer and cyst configuration exhibited the ability to drive net fluid transport in either direction. Monolayers and microcysts reabsorbed fluid in the control state in the absence of cAMP agonists and rapidly reversed the direction of fluid transport to secretion when exposed to forskolin (75, 113, 178) (Table 2).2·h1. Ouabain (10 µM) was added to the cavity medium and forskolin to the bath of another group of 10 cysts. This application of ouabain to the apical surface did not affect the rate of secretion (0.18 ± 0.07 µl·cm2·h1). Both forskolin and ouabain were added to the bath (basolateral surface) of a third group of 10 cysts. The rate of secretion by this group was substantially lower (0.14 ± 0.15 µl·cm2·h1). Similar results were obtained from monolayers of cultured ADPKD cells. Ouabain (0.1 µM) added to the apical surface did not affect forskolin-induced secretion; ouabain added to the basolateral surface greatly inhibited secretion. Thus Na+-K+-ATPase, accessible from the basolateral surface, does participate in the solute transport that drives fluid secretion. 
·cm2; the apical surface was negative with respect to the basolateral surface in all of the monolayers, averaging 0.9 mV, and the Isc registered as a positive current flowing from the apical to the basolateral surface (Table 3). Forskolin increased the conductance, hyperpolarized Vt, and increased Isc. Forskolin (10 µM) also caused a threefold elevation of cAMP in the monolayers (75). The direction of Vt and the Isc before and after administration of forskolin are compatible with cation reabsorption or anion secretion. Because forskolin also stimulates fluid secretion by these monolayers (Table 2), it is apparent that the tissues secrete anion (113). The forskolin-stimulated current was inhibited by basolateral application of ouabain (10 µM) but not by apical application (75). The effect of forskolin on Isc and fluid secretion was also inhibited by basolateral application of bumetanide and by apical application of DPC (113). The forskolin-stimulated Isc was not affected by administration of DIDS to the basolateral surface. Glibenclamide (200 µM) applied to the apical surface reduced Isc by 31% (unpublished data). The effect of these inhibitors suggests that Cl enters the cell via a Na+-Cl or a Na+-K+-2Cl cotransporter and exits via a Cl conductance pathway.
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TABLE 3.
Transepithelial electrical properties of cultured autosomal dominant polycystic kidney disease monolayers
. Monolayers of ADPKD cells were exposed bilaterally to solutions in which Cl was replaced by cyclamate. The absence of Cl reduced Isc, and forskolin did not significantly increase it (178). The Cl efflux rate constant was measured in monolayers of cells grown on a plastic surface and loaded with 36Cl. Forskolin increased the rate constant for that efflux. Diphenylamine-2-carboxylate reduced the control efflux rate constant and prevented the forskolin-induced increase (40). (178). Single ADPKD microcysts (Fig. 3A) were isolated and studied as described in section VIIIA for the MDCK microcyst. Fluid transport was measured by determining changes in cyst cavity volume with time, and cell volume was also monitored. In the control state, cavity volume declined with time at a steady rate for at least 60 min without a change in cell volume, indicating that the cells were reabsorbing fluid (Fig. 3B). The application of forskolin plus IBMX or 8-bromo-cAMP plus IBMX reversed the direction of fluid transport within 5 min, and the secretion was maintained at a steady rate for 60 min. Cell volume rapidly fell when secretion was initiated and did not recover. The loss of cell volume averaged 7.5% after 20 min of exposure to 8-bromo-cAMP and IBMX. Bumetanide rapidly blocked fluid secretion and caused an additional 4.2% loss of cell volume. Fluid secretion resumed after the removal of bumetanide, and cell volume increased 2.6%. Changes in intracellular Cl concentration ([Cl]i) were monitored with the use of the fluorescent indicator 6-methoxy-N-ethylquinolinium chloride (178). No noticeable change in [Cl]i occurred when secretion was initiated with 8-bromo-cAMP. The rapid loss of cell volume without a change in [Cl]i indicated that Cl, as well as water, was lost when secretion was initiated. The effect of inhibiting entry of Cl across the basolateral membrane was tested. Furosemide was used instead of bumetanide because the fluorescence of the latter interfered with the measurement of [Cl]i. Furosemide application in the absence of a secretagogue caused a rapid and transient (<2 min) fall in [Cl]i. The subsequent addition of forskolin plus IBMX caused a fall in [Cl]i that persisted for the duration of the exposure to the secretagogues. Intracellular Cl concentration recovered after the removal of both the secretagogues and furosemide. These results were interpreted to indicate that furosemide inhibition of Cl entry across the basolateral membrane, together with the activation of the efflux mechanism in the apical membrane by forskolin, resulted in the fall of [Cl]i.
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FIG. 3.
A: video image of a cultured autosomal dominant polycystic kidney disease (ADPKD) microcyst surrounded by a thin rim of collagen. Microscope was focused on equatorial plane of cyst. Bar at lower left indicates 10 µm. B: effect of forskolin and IBMX on cavity volume and cell volume of a cultured ADPKD microcyst. Top: cavity volume. Solid lines are regression lines for each period and were used to calculate fluid transport rates. Cyst absorbed fluid at a steady rate of 1.73 nl·min1·cm2 inner surface area1 in control period. Upon superfusion with 10 µM forskolin and 100 µM IBMX, direction of fluid transport rapidly reversed to secretion at a rate of 2.88 nl·min1·cm2. Cell volume was stable throughout control period. Upon initiation of secretion, cell volume rapidly fell 6.2% in first 5 min and an additional 4.5% during remainder of 60-min period. [From Wallace et al. (178). Used with permission from Kidney International.]
in the apical membrane has been investigated extensively. Attention was focused on the possible involvement of the cystic fibrosis transmembrane conductance regulator (CFTR). The Cl channel activity of CFTR and its regulation of other membrane ion channels have been shown to play a central role in Cl and fluid transport by a variety of secretory epithelia (144). Moreover, CFTR is present in the kidney (reviewed in Ref. 155). The mRNA for this molecule has been detected in all nephron segments by reverse transcription PCR. Immunocytochemistry detected its presence in proximal tubule, thin limbs of Henle's loop, and luminal membrane of distal tubule, cortical collecting duct, and the inner medullary collecting duct. Patch-clamp analysis has also confirmed its presence in proximal and distal tubules and in the cortical and inner medullary segments of the collecting tubule. It is also present in ADPKD cystic tissue. Hanaoka et al. (84) used a combination of immunocytochemical and patch-clamp techniques to locate CFTR in cultured cells derived from ADPKD cysts. The cAMP-activated Cl currents displayed a linear current-voltage relationship, insensitivity to DIDS, and sensitivity to glibenclamide and DPC. The anion selectivity sequence was Br > Cl > I > glutamate. These channel characteristics are all identical to those of CFTR. Immunocytochemistry was performed on primary cultures of ADPKD cells using two rabbit polyclonal antibodies directed against human CFTR protein. A punctate pattern of staining over the whole cell and at the cell membrane was detected. In sections of ADPKD kidneys, CFTR was detected in ~60% of the cysts. Within individual cysts, the staining was also heterogeneous; 50-60% of the cells contained detectable CFTR. The protein was predominantly localized to the apical membrane of cyst-lining cells. Brill et al. (20) examined the location of CFTR and Na+-K+-ATPase in the membranes of intact cysts from ADPKD kidneys and monolayers of ADPKD cells cultured from the same kidneys. Both the intact cysts and the monolayers were incubated in culture medium. Some of each preparation was exposed to forskolin, and secretion rates were measured before fixation. Monoclonal antibody 6H raised against the dog kidney -subunit of Na+-K+-ATPase and two rabbit polyclonal antibodies directed against human CFTR protein were used in the immunocytochemical examination by laser scanning confocal microscopy. The Na+-K+-ATPase was found to be exclusively localized to the basolateral membranes of the epithelial cells lining the intact cyst wall, but the intensity of the staining was variable. Staining for the enzyme was confined primarily to the lateral membranes of the cultured cells in the monolayers. However, some basal staining appeared in the monolayers. No apical staining was detected in either preparation. Patchy apical microvillar staining for CFTR was detected in cultured monolayers stimulated to secrete fluid by forskolin. Staining was seen only on the apical surface of these monolayers, but some staining appeared in a punctate pattern in monolayers not stimulated with forskolin. The pattern was consistent with localization in intracellular vesicles. In the cysts dissected from the ADPKD kidney and exposed to forskolin, staining for CFTR was detected on the apical surface of the epithelial cells. The intensity of the staining was variable over the entire wall of the cyst. In monolayers and intact cysts stimulated to secrete fluid, double labeling with the Na+-K+-ATPase antibody and the antibodies for CFTR clearly demonstrated the separation of the two proteins in the cell membranes (Fig. 4). Staining for Na+-K+-ATPase was confined to the basolateral membranes, and staining for CFTR was present only on the apical surfaces.
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FIG. 4.
Simultaneous immunolocalization of Na+-K+-ATPase and cystic fibrosis transmembrane conductance regulator (CFTR) in epithelial cells lining wall of an isolated, intact ADPKD cyst that had been exposed to forskolin. 6H monoclonal antibody directed against 1-isoform of Na+-K+-ATPase (green) and a rabbit polyclonal antibody (red) directed against CFTR were used. Image is a confocal XZ cross-section view. CFTR appears on apical surface, and Na+-K+-ATPase is located primarily on lateral membranes of epithelial cells. [From Brill et al. (20). Copyright 1996 National Academy of Sciences, USA.]
and fluid secretion are tied to the presence and activity of this protein (40). Northern blot hybridization using a human CFTR cDNA probe demonstrated the presence of an ~6.5-kb transcript in total RNA from polarized cultures of ADPKD and HKC cells. Four different antibodies directed against human CFTR were utilized in immunocytochemical analysis of ADPKD monolayers using laser-scanning confocal microscopy to generate three-dimensional images in the z-plane. All of the antibodies showed similar patterns of reactivity. These patterns varied from punctate spots to large patches of reactivity that appeared to cover most of the apical surface of individual cells. The reactivity was largely localized to the apical portions of the cells. It was occasionally found within the cytoplasm but was never observed on the basolateral surface. In additional experiments, monolayers were exposed to different concentrations of sense, antisense, or misantisense oligonucleotides directed against CFTR mRNA for a 12-h period before exposure to forskolin. Fluid transport rates or the abundance of reactive CFTR was then measured. The amount of immunofluorescence (the abundance of reactive CFTR) was quantitated using computer software to determine the number of pixels displaying immunoreactivity in a standard microscopic field. Cystic fibrosis transmembrane conductance regulator abundance was highest in cells treated with forskolin alone and lowest in cells pretreated with the antisense oligonucleotide. Similarly, the rate of forskolin-stimulated fluid secretion was the lowest in the monolayers exposed to the antisense oligonucleotides. Cystic fibrosis transmembrane conductance regulator abundance and fluid secretion measurements for monolayers treated with sense and misantisense oligonucleotides fell in the intermediate range. Both fluid secretion and CFTR abundance were measured in six monolayers treated with forskolin. Two of these were treated with different concentrations of sense oligonucleotide and two with different concentrations of antisense oligonucleotides. The measurements indicated a strong correlation (R2 = 0.96) between the forskolin-induced secretion rate and CFTR abundance. These results support the hypothesis that a direct tie exists between the rate of fluid secretion and the activity of CFTR in ADPKD tissue. entry mechanism is lacking. As described above, this mechanism is inhibited by bumetanide and furosemide. Inhibition of the mechanism, when secretion has been activated, results in loss of cell volume, indicating that the transporter adds net solute to the cell (178). This suggests that an ion-exchange mechanism is not involved. In addition, the basolateral addition of the Cl/HCO3 exchange inhibitor DIDS (100 µM) did not affect the forskolin-stimulated Isc in ADPKD monolayers (11.6 ± 1.3 vs. 10.3 ± 1.5 µA/cm2, n = 5, P > 0.05; unpublished data). It is possible that the transporter is the BSC2 or NKCC1 form of the Na+-K+-2Cl cotransporter that has been identified in the basolateral membrane of the mouse medullary collecting duct cell line (mIMCD-3) (93) and in terminal inner medullary collecting duct segments of the mouse kidney (94).-subunit of guinea pig and dog kidney Na+-K+-ATPase, they detected the enzyme only on the apical membrane of cells lining the cysts. The results of enzyme cytochemical techniques also demonstrated that the Na+-K+-ATPase located in the apical membrane of cyst cells was enzymatically active. The binding of [3H]ouabain to membrane vesicles prepared from normal and ADPKD kidneys was also measured. Ouabain bound exclusively to apical membranes vesicles prepared from cystic tissue. The unidirectional movement of 22Na+ was measured in confluent monolayers of ADPKD cells derived from an explant culture. The rate of movement of 22Na+ from the basal to apical surface greatly exceeded the rate of movement in the opposite direction, as expected for a NaCl-secreting epithelium. That basal to apical movement of 22Na+ was inhibited by addition of 0.1 mM ouabain to the apical medium. This corroborated the results of the enzyme location studies. The authors proposed that fluid secretion by ADPKD cysts is the result of active secretion of Na+ resulting from the mislocation of Na+-K+-ATPase to the apical membrane. -subunit of the canine enzyme, they found staining only in the basolateral membrane of 75% of the cells in cysts lined by cuboidal cells. The enzyme was found in both the apical and basolateral membranes of the remaining cells. Localization of Na+-K+-ATPase exclusively to the apical membrane was not observed in any cysts. However, the enzyme was routinely found largely in the apical membrane of tubular cells in portions of normal parenchyma of human kidneys that were maintained at 20°C for 30 min or longer. This suggests that redistribution of Na+-K+-ATPase can be induced by ischemia during tissue processing. The work of Brill et al. (20), described above, using a monoclonal antibody and laser confocal microscopy found the enzyme confined exclusively to the basolateral surface of ADPKD cyst walls and monolayers formed by cultured cells. The functional studies of the effect of 105 and 107 M concentrations of ouabain on fluid secretion by intact cysts and monolayers and on Isc in the monolayers indicated that ouabain was effective when applied to the basolateral surface but not to the apical surface (75, 190). The direction of Vt and Isc in ADPKD monolayers stimulated to secrete fluid indicated that anion rather than cation is actively secreted (75, 113). is secreted via a cotransport mechanism in the basolateral membrane and CFTR in the apical membrane (Fig. 5, Table 4).
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FIG. 5.
Transport mechanisms involved in Cl and fluid secretion by a variety of secretory epithelia (106). These same mechanisms are thought to be involved in fluid secretion by ADPKD cystic epithelium. Numbers in brackets refer to numbers in first column of Table 4, which summarizes evidence for Cl and fluid secretion and involvement of each transport mechanism in process.
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TABLE 4.
Mechanisms involved in fluid secretion by autosomal dominant polycystic kidney disease tissue
IX. ABSORPTION BY THE CYSTIC EPITHELIUM
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X. DILEMMA POSED BY THE GRADIENT CYST
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concentrations. The mechanism of fluid accumulation by these cysts is unknown. The fluid in these cysts is isosmotic; the nonelectrolyte solutes present include amino acids and a large variety of other organic compounds (59, 61). Gardner et al. (61) have proposed that these solutes originate from dead cells that have desquamated from the cyst wall and have released their cell contents. They have hypothesized that fluid accumulation within cysts, nongradient as well as gradient cysts, is the result of osmotic equilibration of water across the cyst wall coupled with a varying degree of passive influx of Na+. This theory does not take into account the repeated demonstrations of active electrolyte transport by cystic epithelia. and Na+ gradients. During periods when secretagogue levels are low, the absorptive mechanisms may reduce the concentrations of the two electrolytes without generating a large rate of fluid absorption because of the presence of the impermeant solutes (68). Alternatively, activation of Na+ absorption may vary with time. Mineralocorticoid activation of the epithelial Na+ channel (ENaC) could serve to depolarize the apical membrane, reversing the electrochemical gradient that drives Cl secretion.
XI. HEPATIC CYSTS IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
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/HCO3 exchanger, AE2, indicated its presence on the apical surface of cells of small and medium-sized ducts (114). It was postulated that secretin, acting through cAMP, activates CFTR and generates secretion of Cl. Some of the secreted Cl is then considered to be exchanged for HCO3 (31). The composition of ADPKD hepatic cyst fluid obtained by percutaneous puncture did not differ remarkably from that secreted by the normal epithelium (51, 132). Secretin also stimulated fluid secretion by the cystic epithelium but did not alter the pH or the electrolyte composition of the cyst fluid (51). /HCO3 exchanger that functioned as an alkali loader during recovery from an acidic cell pH, and a Na+-independent Cl/HCO3 exchanger that functioned as an alkali extruder (81). The response of the LCDE and IBE cells to an acute removal of Cl from the bathing medium was compared (134). The rate of alkalinization of cell pH as Cl left the cell was significantly slower in the LCDE cells than in the IBE cells. The rate of recovery of cell pH when Cl was reintroduced was also reduced in the LCDE cells. This suggested a reduction in the activity of the Na+-independent Cl/HCO3 exchanger. Northern blot analysis could not detect mRNA for the anion exchanger, AE1, in either cell line, but mRNA for AE2 was detected at similar levels in both cell lines, confirming the earlier observation (114). Immunolocalization studies using an antipeptide antibody to a portion of the AE2 exchanger disclosed a reduced degree of peripheral AE2 in the LCDE cells as compared with the IBE cells. Western immunoblotting with the same antipeptide revealed comparable levels of the core glycosylated AE2 protein in both cell lines. However, there was a decreased abundance of the mature, fully glycosylated form of AE2 in the LCDE cell lines. These results suggest a defect in Golgi glycosylation in the LCDE cells and may explain the inability of the cystic epithelium to alter cyst fluid pH in response to secretin (134). The existence of such a defect in AE2 in renal ADPKD cells has not been investigated. This is the second report of a possible defect in glycosylation of membrane proteins in ADPKD. As described above, Western immunoblot analysis showed a decline in the content of the water channel AQP-2 in early-stage ADPKD kidneys and abnormalities in glycosylation patterns (42).
XII. A CYST ACTIVATING FACTOR PRESENT IN CYST FLUID
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XIII. QUESTIONS REMAINING
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have not been resolved. and fluid secretion, the basolateral Cl uptake mechanism has not been completely identified. There is a strong possibility that it is the secretory NKCC1 form of the Na+-K+-Cl cotransporter, which is present on the basolateral surface of collecting tubular cells in the normal kidney (93, 94). In addition, the possible presence of additional Cl channels that may contribute to Cl and fluid secretion has not been investigated. The nature of the K+ channels that assist in maintaining the driving force for Cl exit from the cell also requires investigation. Research into the receptors and signal transduction pathways involved in stimulation and maintenance of fluid secretion has only begun. Additional knowledge in this area may assist in devising strategies to limit the growth of cysts./HCO3 exchanger, AE2, in cells cultured from ADPKD hepatic cysts and a possible defect in Golgi glycosylation of AE2 by these cells (134) is intriguing. This exchanger is widely expressed in the kidney (2), and the possibility of abnormal activity of expression in ADPKD renal tissue should be examined. It is possible that this may account for the defect in acid secretion that is seen in some ADPKD patients (see sect. V).
XIV. COMPARISON OF THE CYSTIC CELL TO OTHER EPITHELIAL CELLS
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, including a murine IMCD cell line (100, 101) and rat and pig primary IMCD cell cultures (36, 191). channels with the properties of CFTR are present in the proximal tubule, distal tubule, and principal cells of the cortical collecting duct and the IMCD (155). Chloride ion traffic through the CFTR channel may occur in either direction depending on the prevailing electrochemical gradient. The gradients may be altered by activation of the ENaC channel; the inward Na+ current through the channel would depolarize the apical membrane, creating a gradient that would drive Cl in the absorptive direction (155). In contrast, activation of basolateral Cl transporters that move Cl into the cell and/or activation of K+ channels that hyperpolarize the cell would drive a Cl flux in the secretory direction. cotransporter that is found in a murine medullary collecting duct cell line (41) and in the IMCD segments of the murine kidney (94). In primary cultures of rat IMCD cells, a Cl/HCO3 exchanger has been identified as the mechanism involved in the basolateral Cl uptake stimulated by cAMP agonists (191), and in mIMCD-K2 cells, both the Cl/HCO3 exchanger and the Na+-K+-2Cl cotransporter are involved (101). Thus the transport mechanisms so far identified in ADPKD cystic cells and the capacity to secrete Cl are present in some cultured renal epithelial cell lines derived from kidneys in which ADPKD is not present, and they are also present in terminally differentiated cells of renal tubular segments. A major difference may be the reduced, but not absent, ability of the ADPKD cells to absorb fluid. It is not known whether this is because of an absence of the requisite transporters or to altered regulation of the transporters present. via the CFTR channel in response to cAMP agonists and display no inward cation conductance (45). Cells lining the middle of the crypt display a somewhat reduced response to forskolin and a small sensitivity to the Na+ channel blocker amiloride, and cells at the intestinal surface have a higher sensitivity to amiloride and a small sensitivity to forskolin (76). Thus it appears that the colonocytes' ability to secrete Cl diminishes as they maturate and their ability to reabsorb Na+ increases. and fluid throughout gestation and develops the ability to actively reabsorb Na+ only during late gestation (126). The expression of CFTR may diminish in rat fetal lung epithelial cells as gestation progresses (109), and the expression of the ENaC increases (126). and fluid, whereas absorption prevails in terminally differentiated cells. Also in the intestine and in the kidney, as well as in airway epithelium, there are examples of cells, fully matured, that retain the ability to switch from absorption to secretion.
XV. CONCLUSIONS
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drives the fluid secretion. The membrane mechanisms that participate in this secretion include CFTR located in the apical membrane, Na+-K+-ATPase located in the basolateral membrane, and a bumetanide-sensitive Cl entry mechanism also present in the basolateral membrane. Activation of K+ channels may preserve the electrochemical gradient causing efflux of Cl across the apical membrane. In the absence of cAMP agonists, cultured cystic cells display an ability to absorb fluid. The mechanisms generating fluid secretion by the cystic cells are not unique to these cells. The ability to secrete Cl in response to cAMP agonists is present in other renal epithelial cells, notably those in the inner medullary segments of the collecting duct. and fluid, and both types of cells become fluid absorbers as they mature. We suggest that Cl and fluid secretion by cystic cells may be the consequence of the inability of the cells to fully differentiate. The failure of fluid absorption to become the dominating process in the cystic epithelium may not be due to the presence of abnormal transport mechanisms but rather may be the consequence of a failure of absorptive transporters or their control mechanisms to fully develop. Thus the genetic defect in ADPKD may not directly affect transport systems but may arrest the cells in an incompletely differentiated, proliferative state.
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The work by the authors, cited above, was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-13476 and DK-45614, grants-in-aid from the Kansas Affiliate of the American Heart Association, and a grant from the Polycystic Kidney Research Foundation.
Address for reprint requests: L. P. Sullivan, Dept. of Molecular and Integrative Physiology, Univ. of Kansas Medical Center, Kansas City, KS 66160.
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REFERENCES |
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TopPrevious |
|---|
1. AL-AWQATI, Q.. Puzzling polycystin. Mol. Med. 2: 663-664, 1996[Medline].
2.
ALPER, S. L.,
A. K. STUART-TILLEY,
D. BIEMESDERFER,
B. E. SCMUKLER,
AND D. BROWN.
Immunolocalization of AE2 anion exchanger in rat kidney.
Am. J. Physiol.
273(Renal Physiol. 42): F601-F614, 1997
3. ALTON, E. W. F. W. Applied cell biology. In: Cystic Fibrosis, edited by M. E. Hodson and D. M. Geddes. London: Chapman & Hall, 1995, p. 41-73.
4.
AVNER, E. D.,
AND W. E. SWEENEY.
JR., AND W. J. NELSON. Abnormal sodium pump distribution during renal tubulogenesis in congenital murine polycystic kidney disease.
Proc. Natl. Acad. Sci. USA
89: 7447-7451, 1992
5. AVNER, E. D., AND W. E. SWEENEY. JR., N. P. PIESCO, AND D. ELLIS. A new model of glucocorticoid-induced cystic metanephric maldevelopment. Experientia 40: 489-490, 1984[Medline].
6.
BACHINSKY, D. R.,
I. SABOLIC,
D. S. EMMANOUEL,
D. M. JEFFERSON,
F. A. CARONE,
D. BROWN,
AND R. D. PERRONE.
Water channel expression in human ADPKD kidneys.
Am. J. Physiol.
268(Renal Fluid Electrolyte Physiol. 37): F398-F403, 1995
7. BAERT, L.. Hereditary polycystic kidney disease (adult form): a microdissection study of two cases at an early stage of the disease. Kidney Int. 13: 519-525, 1978[Medline].
8.
BARAC-NIETO, M.,
AND J. J. COHEN.
Nonesterified fatty acid uptake by dog kidney: effects of probenecid and chlorothiazide.
Am. J. Physiol.
215: 98-105, 1968
9. BARISONI, L., M. TRUDEL, N. CHRETIEN, L. WARD, J. VAN ADELSBERG, AND V. D'AGATI. Analysis of the role of membrane polarity in polycystic kidney disease of transgenic SBM mice. Am. J. Pathol. 147: 1728-1735, 1995[Abstract].
10. BELL, P. E., K. F. HOSSACK, P. A. GABOW, J. A. DURR, A. M. JOHNSON, AND R. W. SCHRIER. Hypertension in autosomal dominant polycystic kidney disease. Kidney Int. 34: 683-690, 1988[Medline].
11. BENNETT, W. M., L. ELZINGA, J. P. PULLIAM, A. L. RASHAD, AND J. M. BARRY. Cyst fluid antibiotic concentrations in autosomal dominant polycystic kidney disease. Am. J. Kidney Dis. 6: 400-404, 1985[Medline].
12. BERNSTEIN, J. A classification of renal cysts. In: Cystic Disease of the Kidney, edited by K. D. Gardner. New York: Wiley, 1976, p. 7-30.
13. BERNSTEIN, J. Morphology of human renal cystic disease. In: Chronic Renal Disease, edited by N. B. Cummings and S. Klahr. New York: Plenum, 1985, p. 47-54.
14. BIHOREAU, M. T., I. CECCHERINI, J. BROWNE, B. KRANZLIN, G. ROMEO, G. M. LATHROP, M. R. JAMES, AND N. GRETZ. Location of the first genetic locus, PKDr1 controlling autosomal dominant polycystic kidney disease in Han:SPRD cy/+ rat. Hum. Mol. Genet. 4: 609-613, 1997.
15.
BIRENBOIM, N.,
V. S. DONOSO,
R. A. HUSEMAN,
AND J. J. GRANTHAM.
Renal excretion and cyst accumulation of 2micro-globulin in polycystic kidney disease.
Kidney Int.
31: 85-92, 1987[Medline].
16. BJERLE, P., B. LINDQVIST, AND G. MICHAELSON. Pressure measurements in renal cysts. Scand. J. Clin. Lab. Invest. 27: 135-138, 1971[Medline].
17. BRASIER, J. L., AND E. P. HENSKE. Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis. J. Clin. Invest. 99: 194-199, 1997[Medline].
18. BREUER, W. V., E. MACK, AND A. ROTHSTEIN. Activation of K and Cl channels by Ca and cyclic AMP in dissociated kidney epithelial (MDCK) cells. Pflügers Arch. 411: 450-455, 1988[Medline].
19. BRICKER, N. S., AND J. F. PATTON. Cystic disease of the kidneys. A study of dynamics and chemical composition of cyst fluid. Am. J. Med. 18: 207-219, 1955[Medline].
20.
BRILL, S. R.,
K. E. ROSS,
C. J. DAVIDOW,
M. YE,
J. J. GRANTHAM,
AND M. J. CAPLAN.
Immunolocalization of ion transport proteins in human autosomal dominant polycystic kidney epithelial cells.
Proc. Natl. Acad. Sci. USA
93: 10206-10211, 1996
21.
BROWN, C. D. A.,
E. L. RUGG,
AND N. L. SIMMONS.
Loop-diuretic inhibition of adrenaline-stimulated Cl secretion in a cultured epithelium of renal origin (MDCK).
Q. J. Exp. Physiol.
71: 183-193, 1986
22.
BROWN, C. D. A.,
AND N. L. SIMMONS.
Catecholamine-stimulation of Cl secretion in MDCK cell epithelium.
Biochim. Biophys. Acta
649: 427-435, 1981[Medline].
23.
BURN, T. C.,
T. D. CONNORS,
W. R. DACKOWSKI,
L. R. PETRY,
T. J. VAN RAAY,
J. M. MILLHOLLAND,
M. VENET,
G. MILLER,
R. M. HAKIM,
G. M. LANDES,
K. W. KLINGER,
F. QIAN,
L. F. ONUCHIC,
T. WATNICK,
G. G. GERMINO,
AND N. A. DOGGETT.
Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat. The American PKD1 consortium.
Hum. Mol. Genet.
4: 575-582, 1995
24. CALVET, J. P.. Molecular genetics of polycystic kidney disease. J. Nephrol. 11: 24-34, 1998.[Medline]
25. CARONE, F. A., S. NAKAMURA, M. CAPUTO, R. BACALLAO, W. J. NELSON, AND Y. S. KANWAR. Cell polarity in human renal cystic disease. Lab. Invest. 70: 648-655, 1994[Medline].
26. CARONE, F. A., S. NAKAMURA, P. PUNYARIT, Y. S. KANWAR, AND W. J. NELSON. Sequential tubular cell and basement membrane changes in polycystic kidney disease. J. Am. Soc. Nephrol. 3: 244-253, 1992[Abstract].
27. CARONE, F. A., S. OZONO, S. SAMMA, Y. S. KANWAR, AND R. OYASU. Renal functional changes in experimental cystic disease are tubular in origin. Kidney Int. 33: 8-13, 1988[Medline].
28. CARONE, F. A., J. STOLARCZYK, F. A. KRUMLOVSKY, S. G. PERLMAN, T. H. ROBERTS, AND R. G. ROWLAND. The nature of a drug-induced renal concentrating defect in rats. Lab. Invest. 31: 658-664, 1974[Medline].
29. CHAPMAN, A. B., A. JOHNSON, P. A. GABOW, AND R. W. SCHRIER. The renin-angiotensin-aldosterone system and autosomal dominant polycystic kidney disease. N. Engl. J. Med. 323: 1091-1096, 1990[Abstract].
30. CHESTER, A. C., K. GEOLY, G. E. SCHREINER, AND H. G. PREUSS. Early diagnosis of polycystic kidney disease. Am. Family Physician 23: 175-181, 1981.
31. COHN, J. A., T. V. STRONG, M. R. PICCIOTTO, A. C. NAIRN, F. S. COLLINS, AND J. G. FITZ. Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells. Gastroenterology 105: 1857-1864, 1993[Medline].
32. CORNELL, S. C.. Angiography in polycystic disease of the kidney. J. Urol. 103: 24-26, 1970[Medline].
33. COWLEY, B. D., JR., AND V. H. GATTONE II. In vivo models of PKD in non-murine species. In: Polycystic Kidney Disease, edited by M. L. Watson and V. E. Torres. New York: Oxford Univ. Press, 1996, p. 88-110.
34. COWLEY, B. D.. JR., S. GUDAPATY, A. L. KRAYBILL, B. D. BARASH, M. A. HARDING, J. P. CALVET, AND V. H. GATTONE II. Autosomal dominant polycystic kidney disease in the rat. Kidney Int. 43: 522-534, 1993[Medline].
35. CUPPAGE, F. E., R. A. HUSEMAN, A. CHAPMAN, AND J. J. GRANTHAM. Ultrastructure and function of cysts from human adult polycystic kidneys. Kidney Int. 17: 372-381, 1980[Medline].
36. CUTHBERT, A. W., A. M. GEORGE, AND L. MACVINISH. Kinin effects on electrogenic ion transport in primary cultures of pig renal papillary collecting tubule cells. Am. J. Physiol. 249(Renal Fluid Electrolyte Physiol. 18): F439-F447, 1985[Medline].
37. D'ANGELO, A., G. MIONI, E. OSSI, A. LUPO, E. VALVO, AND G. MASCHIO. Alterations in renal tubular sodium and water transport in polycystic kidney diseases. Clin. Nephrol. 3: 99-105, 1975[Medline].
38. DANIELSEN, H., A. H. NIELSEN, E. B. PEDERSEN, P. HERLEVSEN, H. J. KORNERUP, AND V. POSBORG. Exaggerated natriuresis in adult polycystic kidney disease. Acta Med. Scand. 219: 59-66, 1986[Medline].
39. DAOUST, M. C., D. M. REYNOLDS, D. G. BICHET, AND S. SOMLO. Evidence for a third genetic locus for autosomal dominant polycystic kidney disease. Genomics 25: 733-736, 1995[Medline].
40. DAVIDOW, C. J., R. L. MASER, L. A. ROME, J. P. CALVET, AND J. J. GRANTHAM. The cystic fibrosis transmembrane conductance regulator mediates transepithelial fluid secretion by human autosomal dominant polycystic kidney disease epithelium in vitro. Kidney Int. 50: 208-218, 1996[Medline].
41.
DELPIRE, E.,
M. I. RAUCHMAN,
D. R. BEIER,
S. C. HEBERT,
AND S. R. GULLANS.
Molecular cloning and chromosome localization of a putative basolateral Na-K-2Cl cotransporter from mouse inner medullary collecting duct (mIMCD-3) cells.
J. Biol. Chem.
269: 25677-25683, 1994
42.
DEVUYST, O.,
C. R. BURROW,
B. L. SMITH,
P. AGRE,
M. A. KNEPPER,
AND P. D. WILSON.
Expression of aquaporins-1 and -2 during nephrogenesis and in autosomal dominant polycystic kidney disease.
Am. J. Physiol.
271(Renal Fluid Electrolyte Physiol. 40): F169-F183, 1996
43. DOUSA, T. P., R. G. ROWLAND, AND F. A. CARONE. Renal medullary adenylate cyclase in drug-induced nephrogenic diabetes insipidus. Proc. Soc. Exp. Biol. Med. 142: 720-772, 1973[Medline].
44. ECKARDT, K. U., M. MOLLMANN, R. NEUMANN, R. BRUNKHORST, H. U. BURGER, G. LONNEMANN, H. SCHOLZ, G. KEUSCH, B. BUCHHOLZ, U. FREI, C. BAUER, AND A. KURTZ. Erythropoietin in polycystic kidneys. J. Clin. Invest. 84: 1160-1166, 1989.
45.
ECKE, D.,
M. BLEICH,
AND R. GREGER.
Crypt base cells show forskolin-induced Cl secretion but no cation inward conductance.
Pflügers Arch.
431: 427-434, 1996[Medline].
46. ETTINGER, A., P. C. KAHN, AND H. M. WISE. JR. The importance of selective renal angiography in the diagnosis of polycystic disease. J. Urol. 102: 156-161, 1969[Medline].
47. EUROPEAN POLYCYSTIC KIDNEY DISEASE CONSORTIUM. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 77: 881-894, 1994.
48. EVAN, A. P., AND K. D. GARDNER. JR. Nephron obstruction in nordihydroguaiaretic acid-induced renal cystic disease. Kidney Int. 15: 7-19, 1979[Medline].
49. EVAN, A. P., AND K. D. GARDNER, JR. Morphology of polycystic kidney disease in man and experimental models. In: Chronic Renal Disease, edited by N. B. Cummings and S. Klahr. New York: Plenum, 1985, p. 55-68.
50. EVAN, A. P., AND K. D. GARDNER. JR., AND J. BERNSTEIN. Polypoid and papillary epithelial hyperplasia: a potential cause of ductal obstruction in adult polycystic disease. Kidney Int. 16: 743-750, 1979[Medline].
51. EVERSON, G. T., M. EMMETT, W. R. BROWN, P. REDMOND, AND D. THICKMAN. Functional similarities of hepatic cystic and biliary epithelium: studies of fluid constituents and in vivo secretion in response to secretin. Hepatology 11: 557-565, 1990[Medline].
52. FICK, G. M., AND P. A. GABOW. Natural history of autosomal dominant polycystic kidney disease. Annu. Rev. Med. 45: 23-29, 1994[Medline].
53. FORBUSH, B., III, M. HAAS, AND C. LYTLE. Na-K-Cl cotransport in the shark rectal gland. I. Regulation in the intact perfused gland. Am. J. Physiol. 262 (Cell Physiol. 31): C1000-C1008, 1992.
54. GABOW, P. A., A. B. CHAPMAN, A. M. JOHNSON, D. J. TANGEL, I. T. DULEY, W. D. KAEHNY, M. MANCO-JOHNSON, AND R. W. SCHRIER. Renal structure and hypertension in autosomal dominant polycystic kidney disease. Kidney Int. 38: 1177-1180, 1990[Medline].
55. GABOW, P. A., AND J. J. GRANTHAM. Polycystic kidney disease. In: Diseases of the Kidney (6th ed.), edited by R. W. Schrier and C. W. Gottschalk. Boston: Little, Brown, 1996, p. 521-560.
56. GABOW, P. A., A. M. JOHNSON, W. D. KAEHNY, W. J. KIMBERLING, D. C. LEZOTTE, I. T. DULEY, AND R. H. JONES. Factors affecting the progression of renal disease in autosomal dominant polycystic kidney disease. Kidney Int. 41: 1311-1319, 1992[Medline].
57. GABOW, P. A., A. M. JOHNSON, W. D. KAEHNY, M. L. MANCO-JOHNSON, I. T. DULEY, AND G. T. EVERSON. Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease. Hepatology 11: 1033-1037, 1990[Medline].
58. GABOW, P. A., W. D. KAEHNY, A. M. JOHNSON, I. T. DULEY, M. MANCO-JOHNSON, D. C. LEZOTTE, AND R. W. SCHRIER. The clinical utility of renal concentrating capacity in polycystic kidney disease. Kidney Int. 35: 675-680, 1989[Medline].
59. GARDNER, K. D.. JR. Composition of fluid in twelve cysts of a polycystic kidney. N. Engl. J. Med. 281: 985-988, 1969.
60. GARDNER, K. D.. JR., J. S. BURNSIDE, B. J. SKIPPER, S. K. SWAN, W. M. BENNETT, B. A. CONNORS, AND A. P. EVAN. On the probability that kidneys are different in autosomal dominant polycystic disease. Kidney Int. 42: 1199-1206, 1992[Medline].
61.
GARDNER, K. D..
JR., R. H. GLEW, A. P. EVAN, J. A. MCATEER, AND J. BERNSTEIN. Why renal cysts grow.
Am. J. Physiol.
266(Renal Fluid Electrolyte Physiol. 35): F353-F359, 1994
62. GATTONE, V. H., II, J. P. CALVET, B. D. COWLEY, JR., A. P. EVAN, T. S. SHAVER, K. HELMSTADTER, AND J. J. GRANTHAM. Autosomal recessive polycystic kidney disease in a murine model. A gross and microscopic description. Lab. Invest. 59: 231-238, 1988.
63. GATTONE, V. H., II, B. D. COWLEY, JR., B. D. BARASH, S. NAGAO, H. TAKAHASHI, T. YAMAGUCHI, AND J. J. GRANTHAM. Methylprednisolone retards the progression of inherited polycystic kidney disease in rodents. Am. J. Kidney Dis. 25: 302-313, 1995.
64. GATTONE, V. H., II, AND J. J. GRANTHAM. Understanding human cystic disease through experimental models. Semin. Nephrol. 11: 617-631, 1991.
65. GENG, L., Y. SEGAL, B. PEISSEL, N. DENG, Y. PEI, F. CARONE, H. G. RENNKE, A. M. GLUCKSMANN-KUIS, M. C. SCHNEIDER, M. ERICSSON, S. T. REEDERS, AND J. ZHOU. Identification and localization of polycystin, the PKD1 gene product. J. Clin. Invest. 98: 2674-2682, 1996[Medline].
66. GRAHAM, P. C., AND G. B. M. LINDOP. The anatomy of the renin-secreting cell in adult polycystic kidney disease. Kidney Int. 33: 1084-1090, 1988[Medline].
67. GRANTHAM, J. J.. Fluid secretion, cellular proliferation, and the pathogenesis of renal epithelial cysts. J. Am. Soc. Nephrol. 3: 1841-1857, 1993[Abstract].
68. GRANTHAM, J. J.. The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: recent advances. Am. J. Kidney Dis. 28: 788-803, 1996[Medline].
69. GRANTHAM, J. J., V. S. DONOSO, A. P. EVAN, F. A. CARONE, AND K. D. GARDNER. JR. Viscoelastic properties of tubule basement membranes in experimental renal cystic disease. Kidney Int. 32: 187-197, 1987[Medline].
70. GRANTHAM, J. J., J. L. GEISER, AND A. P. EVAN. Cyst formation and growth in autosomal dominant polycystic kidney disease. Kidney Int. 31: 1145-1152, 1987[Medline].
71.
GRANTHAM, J. J.,
P. B. QUALIZZA,
AND R. L. IRWIN.
Net fluid secretion in proximal straight renal tubules in vitro: role of PAH.
Am. J. Physiol.
226: 191-197, 1974
72. GRANTHAM, J. J., G. F. SCHREINER, L. ROME, L. GRENZ, AND A. JOLY. Evidence for inflammatory and secretagogue lipids in cyst fluids from patients with autosomal dominant polycystic kidney disease. Proc. Assoc. Am. Phys. 109: 397-408, 1997.[Medline]
73. GRANTHAM, J. J., M. UCHIC, AND E. J. CRAGOE. JR., J. KORNHAUS, J. A. GRANTHAM, V. DONOSO, R. MANGOO-KARIM, A. EVAN, AND J. MCATEER. Chemical modification of cell proliferation and fluid secretion in renal cysts. Kidney Int. 35: 1379-1389, 1989[Medline].
74. GRANTHAM, J. J., M. YE, C. DAVIDOW, B. HOLUB, AND M. SHARMA. Evidence for a potent lipid secretagogue in the cyst fluids of patients with autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 6: 1242-1249, 1995[Abstract].
75. GRANTHAM, J. J., M. YE, V. H. GATTONE II, AND L. P. SULLIVAN. In vitro fluid secretion by epithelium from polycystic kidneys. J. Clin. Invest. 95: 195-202, 1995.
76.
GREGER, R.,
M. BLEICH,
J. LEIPZIGER,
D. ECKE,
M. MALL,
AND K. KUNZELMANN.
Regulation of ion transport in colonic crypts.
News Physiol. Sci.
12: 62-66, 1997.
77. GREGER, R. E., AND F. SCHLATTER. Mechanism of NaCl secretion in rectal gland tubules of spiny dogfish (Squalus acanthias). 2. Effect of inhibitors. Pflügers Arch. 402: 364-375, 1984[Medline].
78. GRIFFIN, M. D., V. E. TORRES, J. P. GRANDE, AND R. KUMAR. Immunolocalization of polycystin in human tissues and cultured cells. Proc. Assoc. Am. Phys. 108: 185-197, 1996.[Medline]
79. GRIFFIN, M. D., V. E. TORRES, AND R. KUMAR. Cystic kidney diseases. Curr. Opin. Nephrol. Hypertens. 6: 276-283, 1997[Medline].
80. GRIMM, P. C., J. F. CROCKER, D. A. MALATJALIAN, AND M. R. OGBORN. The microanatomy of the intracepatic bile duct in polycystic disease: comparison of the cpk mouse and human. J. Exp. Pathol. 71: 119-131, 1990.
81.
GRUBMAN, S. A.,
R. D. PERRONE,
D. W. LEE,
S. L. MURRAY,
L. C. ROGERS,
L. I. WOLKOFF,
A. E. MULBERG,
V. CHERINGTON,
AND D. M. JEFFERSON.
Regulation of intracellular pH by immortalized human intrahepatic biliary epithelial cell lines.
Am. J. Physiol.
266(Gastrointest. Liver Physiol. 29): G1060-G1070, 1994
82.
HAAS, M..
The Na-K-Cl cotransporters.
Am. J. Physiol.
267(Cell Physiol. 36): C869-C885, 1994
83.
HAAS, M.,
L. G. JOHNSON,
AND R. C. BOUCHER.
Regulation of Na-K-Cl cotransport in cultured canine airway epithelia. A [3H]bumetanide binding study.
Am. J. Physiol.
259(Cell Physiol. 28): C557-C569, 1990
84.
HANAOKA, K.,
O. DEVUYST,
E. M. SCHWIEBERT,
P. D. WILSON,
AND W. B. GUGGINO.
A role for CFTR in human autosomal dominant polycystic kidney disease.
Am. J. Physiol.
270(Cell Physiol. 39): C389-C399, 1996
85. HAYASHI, M., Y. YAMAJI, T. MONKAWA, T. YOSHIDA, H. TSUGANEZAWA, H. SASAMURA, W. KITAJIMA, S. SASAKI, K. ISHIBASHI, F. MAURMO, AND T. SARUTA. Expression and localization of the water channels in human autosomal dominant polycystic kidney disease. Nephron 75: 321-326, 1997[Medline].
86. HEGGO, O.. A microdissection study of cystic disease of the kidneys in adults. J. Pathol. Bacteriol. 91: 311-315, 1966[Medline].
87. HUGHES, J., C. J. WARD, B. PERAL, R. ASPINWALL, K. CLARK, J. L. SAN-MILLAN, V. GAMBLE, AND P. C. HARRIS. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nature Genet. 10: 151-160, 1995[Medline].
88. HUSEMAN, R., A. GRADY, D. WELLING, AND J. GRANTHAM. Macropuncture study of polycystic disease in adult human kidneys. Kidney Int. 18: 375-385, 1980[Medline].
89. HUSTED, R. F., K. A. VOLK, R. D. SIGMUND, AND J. B. STOKES. Anion secretion by the inner medullary collecting duct. Evidence for involvement of the cystic fibrosis transmembrane conductance regulator. J. Clin. Invest. 95: 644-650, 1995.
90.
IBRAGHIMOV-BESKROVNAYA, O.,
W. R. DACKOWSKI,
L. FOGGENSTEINER,
N. COLEMAN,
S. THIRU,
L. R. PETRY,
T. C. BURN,
T. D. CONNORS,
T. VANRAAY,
J. BRADLEY,
F. QIAN,
L. F. ONUCHIC,
T. J. WATNICK,
K. PIONTEK,
R. M. HAKIM,
G. M. LANDES,
G. GERMINO,
R. SANDFORD,
AND K. W. KLINGER.
Polycystin: in vitro synthesis, in vivo tissue expression, and subcellular localization identifies a large membrane associated protein.
Proc. Natl. Acad. Sci. USA
94: 6397-6402, 1997
91. INTERNATIONAL POLYCYSTIC KIDNEY DISEASE CONSORTIUM. Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. Cell 81: 289-298, 1995.
92. JACOBSSON, L., B. LINDQVIST, G. MICHAELSON, AND P. BJERLE. Fluid turnover in renal cysts. Acta Med. Scand. 202: 327-329, 1977[Medline].
93. KAPLAN, M. R., D. B. MOUNT, E. DELPIRE, G. GAMBA, AND S. C. HEBERT. Molecular mechanisms of NaCl cotransport. Annu. Rev. Physiol. 58: 649-668, 1996[Medline].
94. KAPLAN, M. R., M. D. PLOTKIN, D. BROWN, S. C. HEBERT, AND E. DELPIRE. Expression of the mouse Na-K-2Cl cotransporter, mBSC2, in the terminal inner medullary collecting duct, the glomerular and extraglomerular mesangium, and the glomerular afferent arteriole. J. Clin. Invest. 98: 723-730, 1996[Medline].
95. KASPAREIT-RITTINGHAUSEN, J., F. DEERBERG, AND A. WCISLO. Hereditary polycystic kidney disease: adult kidney disease associated with renal hypertension, renal osteodystrophy, and uremic enteritis in SPRD rats. Am. J. Pathol. 139: 693-696, 1991[Medline].
96. KASPAREIT-RITTINGHAUSEN, J., K. RAPP, F. DEERBERG, A. WCISLO, AND C. MESSOW. Hereditary polycystic kidney disease associated with osteorenal syndrome in rats. Vet. Pathol. 26: 195-201, 1989[Abstract].
97. KAWA, G., S. NAGAO, A. YAMAMOTO, K. OMORI, Y. KOMATZ, H. TAKAHASHI, AND Y. TASHIRO. Sodium pump distribution is not reversed in the DBA/2FG-pcy, polycystic kidney disease model mouse. J. Am. Soc. Nephrol. 4: 2040-2049, 1994[Abstract].
98. KEES-FOLTS, D., J. L. SADOW, AND G. F. SCHRIENER. Tubular catabolism of albumin is associated with the release of an inflammatory lipid. Kidney Int. 45: 1697-1709, 1994[Medline].
99. KIMBERLING, W. J., S. KUMAR, P. A. GABOW, J. B. KENYON, C. J. CONOLLY, AND S. SOMLO. Autosomal dominant polycystic kidney disease: localization of the second gene to chromosome 4q13-123. Genomics 18: 467-472, 1993[Medline].
100.
KIZER, N. L.,
B. LEWIS,
AND B. A. STANTON.
Electrogenic sodium absorption and chloride secretion by an inner medullary collecting duct cell line (mIMCD-K2).
Am. J. Physiol.
268(Renal Fluid Electrolyte Physiol. 37): F347-F355, 1995
101.
KIZER, N. L.,
D. VANDORPE,
B. LEWIS,
B. BUNTING,
J. RUSSELL,
AND B. A. STANTON.
Vasopressin and cAMP stimulate electrogenic chloride secretion in an IMCD cell line.
Am. J. Physiol.
268(Renal Fluid Electrolyte Physiol. 37): F854-F861, 1995
102. KOLB, H. A., C. D. A. BROWN, AND H. MURER. Identification of a voltage-dependent anion channel in the apical membrane of a Cl-secretory epithelium (MDCK). Pflügers Arch. 403: 262-265, 1985[Medline].
103. LAMBERT, P. P.. Polycystic disease of the kidney. A review. Arch. Pathol. 44: 34-58, 1947.
104. LANG, F., M. DEFREGGER, AND M. PAULMICHL. Apparent chloride conductance of subconfluent Madin Darby canine kidney cells. Pflügers Arch. 407: 158-162, 1986[Medline].
105.
LENZEN, R.,
A. GIANFRANCO,
AND N. TAVOLONI.
Secretin stimulates bile ductular secretory activity through the cAMP system.
Am. J. Physiol.
263(Gastrointest. Liver Physiol. 26): G527-G532, 1992
106. LIEDTKE, C. M.. Regulation of chloride transport in epithelia. Annu. Rev. Physiol. 51: 143-160, 1989[Medline].
107. LYTLE, C., AND B. FORBUSH III. Na-K-Cl cotransport in the shark rectal gland. II. Regulation in isolated tubules. Am. J. Physiol. 262 (Cell Physiol. 31): C1009-C1017, 1992.
108. MACIAS, W. L., J. A. MCATEER, G. A. TANNER, A. L. FRITZ, AND W. M. ARMSTRONG. NaCl transport by Madin Darby canine kidney cyst epithelial cells. Kidney Int. 42: 308-319, 1992[Medline].
109. MACLEOD, R. J., J. R. HAMILTON, H. KOPELMAN, AND N. B. SWEEZEY. Developmental differences of cystic fibrosis transmembrane conductance regulator functional expression in isolated rat fetal distal airway epithelial cells. Pediatr. Res. 35: 45-49, 1994[Medline].
110. MANGOO-KARIM, R., L. P. SULLIVAN, M. YE, AND J. J. GRANTHAM. In vitro models in the study of renal cystogenesis. In: Polycystic Kidney Disease, edited by M. L. Watson and V. E. Torres. New York: Oxford Univ. Press, 1996, p. 39-61.
111. MANGOO-KARIM, R., M. E. UCHIC, M. GRANT, W. A. SHUMATE, J. P. CALVET, C. H. PARK, AND J. J. GRANTHAM. Renal epithelial fluid secretion and cyst growth: the role of cyclic AMP. FASEB J. 3: 2629-2632, 1989[Abstract].
112.
MANGOO-KARIM, R.,
M. UCHIC,
C. LECHENE,
AND J. J. GRANTHAM.
Renal epithelial cyst formation and enlargement in vitro: dependence on cAMP.
Proc. Natl. Acad. Sci. USA
86: 6007-6011, 1989
113.
MANGOO-KARIM, R.,
M. YE,
D. P. WALLACE,
J. J. GRANTHAM,
AND L. P. SULLIVAN.
Anion secretion drives fluid secretion by monolayers of cultured human polycystic cells.
Am. J. Physiol.
269(Renal Fluid Electrolyte Physiol. 38): F381-F388, 1995
114. MARTINEZ-ANSO, E., J. E. CASTILLO, J. DIEZ, J. F. MEDINA, AND J. PRIETO. Immunohistochemical detection of chloride/bicarbonate anion exchangers in human liver. Hepatology 19: 1400-1406, 1994[Medline].
115. MARTINEZ-MALDONADO, M. Functional aspects: electrolyte and uric acid excretion. In: Problems in Diagnosis and Management of Polycystic Kidney Disease, edited by K. D. Gardner, Jr., and J. J. Grantham. Kansas City, KS: PKR Found., 1985, p. 70-80.
116. MARTINEZ-MALDONADO, M., J. J. YIUM, G. EKNOYAN, AND W. N. SUKI. Adult polycystic kidney disease: studies of the defect in urine concentration. Kidney Int. 2: 107-113, 1972[Medline].
117. MCATEER, J. A., F. A. CARONE, J. J. GRANTHAM, S. A. KEMPSON, AND K. D. GARDNER. JR., AND A. P. EVAN. Explant culture of human polycystic kidney. Lab. Invest. 59: 126-136, 1988[Medline].
118. MCATEER, J. A., A. P. EVAN, AND E. L. GARDNER. Morphogenetic clonal growth of kidney epithelial cell line, MDCK. Anat. Rec. 217: 229-239, 1987[Medline].
119. MCDONALD, R. A., AND E. D. AVNER. Mouse models of polycystic kidney disease. In: Polycystic Kidney Disease, edited by M. L. Watson and V. E. Torres. New York: Oxford Univ. Press, 1996, p. 64-87.
120. MILUTINOVIC, J., L. C. AGODOA, R. E. CUTLER, AND G. E. STRIKER. Autosomal dominant polycystic kidney disease. Early diagnosis and consideration of pathogenesis. Am. J. Clin. Pathol. 73: 740-747, 1980[Medline].
121. MOCHIZUKI, T., G. WU, T. HAYASHI, S. L. XENOPHONTOS, B. VELDHUISEN, J. J. SARIS, D. M. REYNOLDS, Y. CAI, P. A. GABOW, A. PIERIDES, W. J. KIMBERLING, M. H. BREUNING, C. C. DELTAS, D. J. PETERS, AND S. SOMLO. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272: 1339-1342, 1996[Abstract].
122.
NAUTA, J.,
M. A. GOEDBLOED,
T. M. LUIDER,
A. T. HOOGEVEEN,
A. M. VAN DEN OUWELAND,
AND D. J. HALLEY.
The Han:SPRD rat is not a genetic model of human autosomal dominant polycystic kidney disease type 1.
Lab. Anim.
31: 241-247, 1997
123. NEUFELD, T. K., D. DOUGLASS, M. GRANT, M. YE, F. SILVA, T. NADASDY, AND J. J. GRANTHAM. In vitro formation and expansion of cysts derived from human renal cortex epithelial cells. Kidney Int. 41: 1222-1236, 1992[Medline].
124. NEUFELD, T. K., M. E. GRANT, AND J. J. GRANTHAM. A method to measure the rate of net fluid secretion by monolayers of cultured renal epithelial cells. J. Tissue Culture Methods 13: 229-234, 1991.
125. NEUFELD, T. K., AND J. J. GRANTHAM. Epidermal growth factor promotes cyst formation by human renal epithelial cells in vitro. Trans. Assoc. Am. Phys. 80: 48-52, 1990.
126. O'BRODOVICH, H. M.. Immature epithelial Na+ channel expression is one of the pathogenetic mechanisms leading to human neonatal respiratory distress syndrome. Proc. Assoc. Am. Phys. 108: 345-355, 1996.[Medline]
127. OGBORN, M. R., S. SAREEN, AND P. C. GRIMM. Renal tubule Na,K-ATPase polarity in glucocorticoid-induced polycystic kidney disease. J. Histochem. Cytochem. 41: 555-558, 1993[Abstract].
128.
OGBORN, M. R.,
S. SAREEN,
J. PRYCHITKO,
R. BUIST,
AND J. PEELING.
Altered organic anion and osmolyte content and excretion in rat polycystic kidney disease: an NMR study.
Am. J. Physiol.
272(Renal Physiol. 41): F63-F69, 1997
129. OGBORN, M. R., S. SAREEN, K. TOMOBE, H. TAKAHASHI, AND J. F. CROCKER. Renal tubule Na,K-ATPase polarity in different animal models of polycystic kidney disease. J. Histochem. Cytochem. 43: 785-790, 1995[Abstract].
130. PALSSON, R., C. P. SHARMA, K. KIM, M. MCLAUGHLIN, D. BROWN, AND M. A. ARNAOUT. Characterization and cell distribution of polycystin, the product of autosomal dominant polycystic kidney disease gene 1. Mol. Med. 2: 702-711, 1996[Medline].
131. PARFREY, P. S., J. C. BEAR, J. MORGAN, B. C. CRAMER, P. J. MCMANAMON, M. H. GAULT, D. N. CHURCHILL, M. SINGH, R. HEWITT, S. SOMLO, AND S. T REEDERS. The diagnosis and prognosis of autosomal dominant polycystic kidney disease. N. Engl. J. Med. 323: 1085-1090, 1990.
132. PATTERSON, M., J. C. GONZALEZ-VITALE, AND C. J. FAGAN. Polycystic liver disease: a study of cyst fluid constituents. Hepatology 2: 475-478, 1982[Medline].
133. PERRONE, R. D.. In vitro function of cyst epithelium from human polycystic kidney. J. Clin. Invest. 76: 1688-1691, 1985.
134.
PERRONE, R. D.,
S. A. GRUBMAN,
S. L. MURRAY,
D. W. LEE,
S. L. ALPER,
AND D. M. JEFFERSON.
Autosomal dominant polycystic kidney disease decreases anion exchanger activity.
Am. J. Physiol.
272(Cell Physiol. 41): C1748-C1756, 1997
135.
PERRONE, R. D.,
S. A. GRUBMAN,
L. C. ROGERS,
D. W. LEE,
E. MOY,
S. L. MURRAY,
V. E. TORRES,
AND D. M. JEFFERSON.
Continuous epithelial cell lines from ADPKD liver cysts exhibit characteristics of intrahepatic biliary epithelium.
Am. J. Physiol.
269(Gastrointest. Liver Physiol. 32): G335-G345, 1995
136. PERRONE, R. D., AND M. L. MCLAUGHLIN. Cyst function in polycystic kidney disease: nongradient cysts. Clin. Nephrol. 32: 113-118, 1989[Medline].
137. PETER, K. Rekonstruktionsmethoden. In: Handbuch der biologischen Arbeits-methoden, edited by E. Abderhalden. Vienna: Urban & Schwarzenberg, 1921, vol. 9, p. 1.
138. POTTER, E. L. Normal and Abnormal Development of the Kidney. Chicago, IL: Year Book, 1972, p. 182-208.
139. PREUSS, H., K. GEOLY, M. JOHNSON, A. CHESTER, A. KLIGER, AND G. SCHREINER. Tubular function in adult polycystic kidney disease. Nephron 24: 198-204, 1979[Medline].
140. QIAN, F., F. J. GERMINO, Y. CAI, X. ZHANG, S. SOMLO, AND G. G. GERMINO. PKD1 interacts with PKD2 through a probable coiled-coil domain. Nature Genet. 16: 179-183, 1997[Medline].
141. QIAN, F., T. J. WATNICK, L. F. ONUCHIC, AND G. G. GERMINO. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell 87: 979-987, 1996[Medline].
142. RAMOS, A., V. E. TORRES, K. E. HOLLEY, K. P. OFFORD, J. RAKELA, AND E. HOLLEY. The liver in autosomal dominant polycystic kidney disease. Arch. Pathol. Lab. Med. 114: 180-184, 1990[Medline].
143. REEDERS, S. T., M. H. BREUNING, K. E. DAVIES, R. D. NICHOLS, A. P. JARMAN, D. R. HIGGS, P. L. PEARSON, AND D. J. WEATHERALL. A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature 317: 542-544, 1985[Medline].
144. RIORDAN, J. R.. The cystic fibrosis transmembrane conductance regulator. Annu. Rev. Physiol. 55: 609-630, 1993[Medline].
145. ROCHA, A. S., AND L. H. KUDO. Factors governing sodium and chloride transport across the inner medullary collecting duct. Kidney Int. 38: 654-667, 1990[Medline].
146. SCHAEFER, K., N. GRETZ, M. BADER, I. OBERBAEUMER, K. U. ECKARDT, W. KRIZ, AND S. BACHMANN. Characterization of the Han:SPRD rat model for hereditary polycystic kidney disease. Kidney Int. 46: 134-152, 1994[Medline].
147. SCHMID, M., J. F. E. MANN, G. STEIN, M. HERTER, J. NUSSBERGER, A. KLINGBEIL, AND E. RITZ. Natriuresis-pressure relationship in polycystic kidney disease. J. Hypertens. 8: 277-283, 1990[Medline].
148.
SCHNERMANN, J.,
J. BRIGGS,
AND G. SCHUBERT.
In situ studies of the distal convoluted tubule in the rat. I. Evidence for NaCl secretion.
Am. J. Physiol.
243(Renal Fluid Electrolyte Physiol. 12): F160-F166, 1982
149. SCHREINER, G. F.. Renal toxicity of albumin and other lipoproteins. Curr. Opin. Nephrol. Hypertens. 4: 369-373, 1995[Medline].
150. SCHWAB, S., D. HINTHORN, D. DIEDERICH, F. CUPPAGE, AND J. GRANTHAM. pH-dependent accumulation of clindamycin in a polycystic kidney. Am. J. Kidney Dis. 3: 63-66, 1983[Medline].
151.
SIMMONS, N. L..
Stimulation of Cl secretion by exogenous ATP in cultured MDCK epithelial monolayers.
Biochim. Biophys. Acta
646: 231-242, 1981[Medline].
152.
SIMMONS, N. L..
Chloride secretion stimulated by prostaglandin E1 and by forskolin in a canine renal epithelial cell line.
J. Physiol. (Lond.)
432: 459-472, 1991
153.
SIMMONS, N. L..
Renal epithelial Cl secretion.
Exp. Physiol.
78: 117-137, 1993[Medline].
154.
SONNENBERG, H..
Secretion of salt and water into the medullary collecting duct of Ringer-infused rats.
Am. J. Physiol.
228: 565-568, 1975
155. STANTON, B. A.. Cystic fibrosis transmembrane conductance regulator (CFTR) and renal function. Wien. Klin. Wochenschr. 109: 457-464, 1997[Medline].
156. STEIN, J. H., R. W. OSGOOD, AND R. T. KUNAU. Direct measurement of papillary collecting duct sodium transport in the rat. Evidence for heterogeneity of nephron function during Ringer loading. J. Clin. Invest. 58: 767-773, 1976.
157. SULLIVAN, L. P., AND J. J. GRANTHAM. Specificity of basolateral organic anion exchange in proximal tubule for cellular and extracellular solutes. J. Am. Soc. Nephrol. 2: 1192-1200, 1992[Abstract].
158. SULLIVAN, L. P., D. P. WALLACE, AND J. J. GRANTHAM. Coupling of cell volume and membrane potential changes to fluid secretion in a model of renal cysts. Kidney Int. 45: 1369-1380, 1994[Medline].
159. SULLIVAN, L. P., D. P. WALLACE, AND J. J. GRANTHAM. Chloride and fluid secretion in polycystic kidney disease. J. Am. Soc. Nephrol. 9: 903-916, 1998[Medline].
160. TAKAHASHI, H., J. P. CALVET, D. DITTEMORE-HOOVER, K. YOSHIDA, J. J. GRANTHAM, AND V. H. GATTONE II. A hereditary model of slowly progressive polycystic kidney disease in the mouse. J. Am. Soc. Nephrol. 1: 980-981, 1991.
161. TAKAHASHI, M., K. TSUCHIYA, Y. KOMATSU, AND H. NIHEI. A role for Na/K adenosine triphosphatase in the pathogenesis of cyst formation in experimental polycystic kidney disease. J. Lab. Clin. Med. 129: 517-526, 1997[Medline].
162. TANNER, G. A., N. GRETZ, B. A. CONNORS, A. P. EVAN, AND M. STEINHAUSEN. Role of obstruction in autosomal dominant polycystic kidney disease in rats. Kidney Int. 50: 873-886, 1996[Medline].
163. TANNER, G. A., N. GRETZ, Y. Z. SHAO, A. P. EVAN, AND M. STEINHAUSEN. Organic anion secretion in polycystic kidney disease. J. Am. Soc. Nephrol. 8: 1222-1231, 1997[Abstract].
164. TANNER, G. A., M. R. MAXWELL, AND J. A. MCATEER. Fluid transport in a cultured cell model of kidney epithelial cyst enlargement. J. Am. Soc. Nephrol. 2: 1208-1218, 1991[Abstract].
165. TANNER, G. A., AND J. A. MCATEER. Measurement of cell volume and fluid transport in MDCK cysts by video microscopy. J. Tissue Culture Methods 13: 235-240, 1991.
166. TANNER, G. A., P. F. MCQUILLAN, M. R. MAXWELL, J. K. KECK, AND J. A. MCATEER. An in vitro test of the cell stretch-proliferation hypothesis of renal cyst enlargement. J. Am. Soc. Nephrol. 6: 1230-1241, 1995[Abstract].
167.
TAUB, M.,
L. CHUMAN,
M. H. SAIER,
AND G. SATO.
Growth of Madin-Darby canine kidney epithelial cell (MDCK) line in hormone-supplemented, serum-free medium.
Proc. Natl. Acad. Sci. USA
76: 3338-3342, 1979
168. TORRES, V. E., D. S. KEITH, K. P. OFFORD, S. P. KON, AND D. M. WILSON. Renal ammonia in autosomal dominant polycystic kidney disease. Kidney Int. 45: 1745-1753, 1994[Medline].
169. TORRES, V. E., D. M. WILSON, AND J. C. BURNETT. JR., C. M. JOHNSON, AND K. P. OFFORD. Effect of inhibition of converting enzyme on renal hemodynamics and sodium management in polycystic kidney disease. Mayo Clin. Proc. 66: 1010-1017, 1991[Medline].
170. TORRES, V. E., D. M. WILSON, K. P. OFFORD, AND J. C. BURNETT. JR., AND J. C. ROMERO. Natriuretic response to volume expansion in polycystic kidney disease. Mayo Clin. Proc. 64: 509-515, 1989[Medline].
171.
TRIMBLE, M. E..
Mediated transport of long-chain fatty acids by rat renal basolateral membranes.
Am. J. Physiol.
257(Renal Fluid Electrolyte Physiol. 26): F539-F546, 1989
172.
TSIOKAS, L.,
E. KIM,
T. ARNOULD,
Y. P. SUKHATME,
AND G. WALZ.
Homo and hetero-dimeric interactions between the gene products of Pkd1 and Pkd2.
Proc. Natl. Acad. Sci. USA
94: 6965-6970, 1997
173. ULLRICH, K. J., G. RUMRICH, AND S. KLOSS. Contraluminal para-aminohippurate transport in the proximal tubule of the rat kidney. III. Specificity: monocarboxylic acids. Pflügers Arch. 409: 547-554, 1987[Medline].
174.
VAN ADELSBERG, J.,
S. CHAMBERLAIN,
AND V. D'AGATI.
Polycystin expression is temporally and spatially regulated during renal development.
Am. J. Physiol.
272(Renal Physiol. 41): F602-F609, 1997
175. VAN ADELSBERG, J. S., AND D. FRANK. The PKD1 gene produces a developmentally regulated protein in mesenchyme and vasculature. Nature Med. 1: 359-364, 1995[Medline].
176. WAITMAN, A. M., W. P. DYCK, AND H. D. JANOWITZ. Effect of secretin and acetazolamide on the volume and electrolyte composition of hepatic bile in man. Gastroenterology 56: 286-294, 1969[Medline].
177.
WALL, S. M.,
J. M. SANDS,
M. F. FLESSNER,
H. NONOGUCHI,
K. R. SPRING,
AND M. A. KNEPPER.
Net acid transport by isolated perfused inner medullary collecting ducts.
Am. J. Physiol.
258(Renal Fluid Electrolyte Physiol. 27): F75-F84, 1990
178. WALLACE, D. P., J. J. GRANTHAM, AND L. P. SULLIVAN. Chloride and fluid secretion by cultured human polycystic kidney cells. Kidney Int. 50: 1327-1336, 1996[Medline].
179. WELLING, L. W., AND J. J. GRANTHAM. Physical properties of isolated perfused renal tubules and tubular basement membranes. J. Clin. Invest. 51: 1063-1075, 1972.
180. WELLING, L. W., AND D. J. WELLING. Kinetics of cyst development in cystic renal disease. In: Chronic Renal Disease, edited by N. B. Cummings and S. Klahr. New York: Plenum, 1985, p. 95-103.
181. WELSH, M.. Barium inhibition of basolateral membrane potassium conductance in tracheal epithelium. Am. J. Physiol. 244(Renal Fluid Electrolyte Physiol. 13): F639-F645, 1983[Medline].
182. WICKRE, C. G., AND W. M. BENNETT. Renal cyst epithelial transport in non-uremic polycystic kidney disease. Kidney Int. 23: 514-518, 1983[Medline].
183. WILSON, P. D. Pathogenesis of polycystic kidney disease: altered cell function. In: Polycystic Kidney Disease, edited by M. L. Watson and V. E. Torres. New York: Oxford Univ. Press, 1996, p. 125-166.
184.
WILSON, P. D..
Epithelial cell polarity and disease.
Am. J. Physiol.
272(Renal Physiol. 41): F434-F442, 1997
185. WILSON, P. D., R. W. SCHRIER, R. D. BRECKON, AND P. A. GABOW. A new method for studying human polycystic kidney disease epithelia in culture. Kidney Int. 30: 371-378, 1986[Medline].
186.
WILSON, P. D.,
A. C. SHERWOOD,
K. PALLA,
J. DU,
R. WATSON,
AND J. T. NORMAN.
Reversed polarity of Na+-K+-ATPase: mislocation to apical plasma membranes in polycystic kidney disease epithelia.
Am. J. Physiol.
260(Renal Fluid Electrolyte Physiol. 29): F420-F430, 1991
187.
WINGO, C. S..
Active and passive chloride transport by the rabbit cortical collecting duct.
Am. J. Physiol.
258(Renal Fluid Electrolyte Physiol. 27): F1388-F1393, 1990
188. YAMAGUCHI, T., S. NAGAO, H. TAKAHASHI, M. YE, AND J. J. GRANTHAM. Cyst fluid from a murine model of polycystic kidney disease stimulates fluid secretion, cyclic adenosine monophosphate accumulation, and cell proliferation by Madin-Darby canine kidney cells in vitro. Am. J. Kidney Dis. 25: 471-477, 1995[Medline].
189. YE, M., M. GRANT, M. SHARMA, L. ELZINGA, S. SWAN, V. E. TORRES, AND J. J. GRANTHAM. Cyst fluid from human autosomal dominant polycystic kidneys promotes cyst formation and expansion by renal epithelial cells in vitro. J. Am. Soc. Nephrol. 3: 984-994, 1992[Abstract].
190.
YE, M.,
AND J. J. GRANTHAM.
The secretion of fluid by renal cysts from patients with autosomal dominant polycystic kidney disease.
N. Engl. J. Med.
329: 310-313, 1993
191.
ZHANG, C.,
R. F. HUSTED,
AND J. B. STOKES.
Effect of cAMP agonists on cell pH and anion transport by cultured rat inner medullary collecting duct cells.
Am. J. Physiol.
270(Renal Fluid Electrolyte Physiol. 39): F131-F140, 1996
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N. Markadieu, R. Crutzen, D. Blero, C. Erneux, and R. Beauwens Hydrogen peroxide and epidermal growth factor activate phosphatidylinositol 3-kinase and increase sodium transport in A6 cell monolayers Am J Physiol Renal Physiol, June 1, 2005; 288(6): F1201 - F1212. [Abstract] [Full Text] [PDF]
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I. E. Veizis and C. U. Cotton Abnormal EGF-dependent regulation of sodium absorption in ARPKD collecting duct cells Am J Physiol Renal Physiol, March 1, 2005; 288(3): F474 - F482. [Abstract] [Full Text] [PDF]
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Q. Tong and J. D. Stockand Receptor tyrosine kinases mediate epithelial Na+ channel inhibition by epidermal growth factor Am J Physiol Renal Physiol, January 1, 2005; 288(1): F150 - F161. [Abstract] [Full Text] [PDF]
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 S. Puri, B. S. Magenheimer, R. L. Maser, E. M. Ryan, C. A. Zien, D. D. Walker, D. P. Wallace, S. J. Hempson, and J. P. Calvet Polycystin-1 Activates the Calcineurin/NFAT (Nuclear Factor of Activated T-cells) Signaling Pathway J. Biol. Chem., December 31, 2004; 279(53): 55455 - 55464. [Abstract] [Full Text] [PDF]
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M. Loghman-Adham, C. E. Soto, T. Inagami, and L. Cassis The intrarenal renin-angiotensin system in autosomal dominant polycystic kidney disease Am J Physiol Renal Physiol, October 1, 2004; 287(4): F775 - F788. [Abstract] [Full Text] [PDF]
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T. Yamaguchi, D. P. Wallace, B. S. Magenheimer, S. J. Hempson, J. J. Grantham, and J. P. Calvet Calcium Restriction Allows cAMP Activation of the B-Raf/ERK Pathway, Switching Cells to a cAMP-dependent Growth-stimulated Phenotype J. Biol. Chem., September 24, 2004; 279(39): 40419 - 40430. [Abstract] [Full Text] [PDF]
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 D. N. Sheppard CFTR Channel Pharmacology: Novel Pore Blockers Identified by High-throughput Screening J. Gen. Physiol., July 26, 2004; 124(2): 109 - 113. [Full Text] [PDF]
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H. F. Cantiello Regulation of calcium signaling by polycystin-2 Am J Physiol Renal Physiol, June 1, 2004; 286(6): F1012 - F1029. [Abstract] [Full Text] [PDF]
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C. J. Venglarik, Z. Gao, and X. Lu Evolutionary Conservation of Drosophila Polycystin-2 as a Calcium-Activated Cation Channel J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1168 - 1177. [Abstract] [Full Text] [PDF]
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K. W. Beyenbach Kidneys sans glomeruli Am J Physiol Renal Physiol, May 1, 2004; 286(5): F811 - F827. [Abstract] [Full Text] [PDF]
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S. Wang, Y. Luo, P. D. Wilson, G. B. Witman, and J. Zhou The Autosomal Recessive Polycystic Kidney Disease Protein Is Localized to Primary Cilia, with Concentration in the Basal Body Area J. Am. Soc. Nephrol., March 1, 2004; 15(3): 592 - 602. [Abstract] [Full Text] [PDF]
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E. I. Veizis, C. R. Carlin, and C. U. Cotton Decreased amiloride-sensitive Na+ absorption in collecting duct principal cells isolated from BPK ARPKD mice Am J Physiol Renal Physiol, February 1, 2004; 286(2): F244 - F254. [Abstract] [Full Text] [PDF]
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S. S. Wildman, K. M. Hooper, C. M. Turner, J. S. K. Sham, E. G. Lakatta, B. F. King, R. J. Unwin, and M. Sutters The isolated polycystin-1 cytoplasmic COOH terminus prolongs ATP-stimulated Cl- conductance through increased Ca2+ entry Am J Physiol Renal Physiol, December 1, 2003; 285(6): F1168 - F1178. [Abstract] [Full Text]
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 O. Devuyst, A. Persu, and M.-T. Vo-Cong Autosomal dominant polycystic kidney disease: modifier genes and endothelial dysfunction Nephrol. Dial. Transplant., November 1, 2003; 18(11): 2211 - 2215. [Full Text] [PDF]
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D. Zheng, M. Wolfe, B. D. Cowley Jr., D. P. Wallace, T. Yamaguchi, and J. J. Grantham Urinary Excretion of Monocyte Chemoattractant Protein-1 in Autosomal Dominant Polycystic Kidney Disease J. Am. Soc. Nephrol., October 1, 2003; 14(10): 2588 - 2595. [Abstract] [Full Text] [PDF]
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A. K. Rajasekaran and S. A. Rajasekaran Role of Na-K-ATPase in the assembly of tight junctions Am J Physiol Renal Physiol, September 1, 2003; 285(3): F388 - F396. [Abstract] [Full Text] [PDF]
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B. Hocher, P. Kalk, T. Slowinski, M. Godes, A. Mach, S. Herzfeld, D. Wiesner, P. C. Arck, H.-H. Neumayer, and B. Nafz ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease J. Am. Soc. Nephrol., February 1, 2003; 14(2): 367 - 376. [Abstract] [Full Text] [PDF]
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 D. Morgan, L. Eley, J. Sayer, T. Strachan, L. M. Yates, A. S. Craighead, and J. A. Goodship Expression analyses and interaction with the anaphase promoting complex protein Apc2 suggest a role for inversin in primary cilia and involvement in the cell cycle Hum. Mol. Genet., December 15, 2002; 11(26): 3345 - 3350. [Abstract] [Full Text] [PDF]
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O. Devuyst and W. B. Guggino Chloride channels in the kidney: lessons learned from knockout animals Am J Physiol Renal Physiol, December 1, 2002; 283(6): F1176 - F1191. [Abstract] [Full Text] [PDF]
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 X.D. Gong, P. Linsdell, K.H. Cheung, G.P.H. Leung, and P.Y.D. Wong Indazole Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator Cl- Channels in Rat Epididymal Epithelial Cells Biol Reprod, December 1, 2002; 67(6): 1888 - 1896. [Abstract] [Full Text] [PDF]
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D. P. Wallace, M. Christensen, G. Reif, F. Belibi, B. Thrasher, D. Herrell, and J. J. Grantham Electrolyte and fluid secretion by cultured human inner medullary collecting duct cells Am J Physiol Renal Physiol, December 1, 2002; 283(6): F1337 - F1350. [Abstract] [Full Text] [PDF]
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L. P. Sullivan, D. P. Wallace, T. Gover, P. A. Welling, T. Yamaguchi, R. Maser, J. W. Eppler, and J. J. Grantham Sulfonylurea-Sensitive K+ Transport is Involved in Cl- Secretion and Cyst Growth by Cultured ADPKD Cells J. Am. Soc. Nephrol., November 1, 2002; 13(11): 2619 - 2627. [Abstract] [Full Text] [PDF]
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F. A. Belibi, D. P. Wallace, T. Yamaguchi, M. Christensen, G. Reif, and J. J. Grantham The Effect of Caffeine on Renal Epithelial Cells from Patients with Autosomal Dominant Polycystic Kidney Disease J. Am. Soc. Nephrol., November 1, 2002; 13(11): 2723 - 2729. [Abstract] [Full Text] [PDF]
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B. A. Watts III and D. W. Good ERK mediates inhibition of Na+/H+ exchange and HCO3- absorption by nerve growth factor in MTAL Am J Physiol Renal Physiol, June 1, 2002; 282(6): F1056 - F1063. [Abstract] [Full Text] [PDF]
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Z. Cai and D. N. Sheppard Phloxine B Interacts with the Cystic Fibrosis Transmembrane Conductance Regulator at Multiple Sites to Modulate Channel Activity J. Biol. Chem., May 24, 2002; 277(22): 19546 - 19553. [Abstract] [Full Text] [PDF]
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J. J. Grantham and D. P. Wallace Return of the secretory kidney Am J Physiol Renal Physiol, January 1, 2002; 282(1): F1 - F9. [Abstract] [Full Text] [PDF]
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D. P. Wallace, L. A. Rome, L. P. Sullivan, and J. J. Grantham cAMP-dependent fluid secretion in rat inner medullary collecting ducts Am J Physiol Renal Physiol, June 1, 2001; 280(6): F1019 - F1029. [Abstract] [Full Text] [PDF]
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G.P.H. Leung, X.D. Gong, K.H. Cheung, S.B. Cheng-Chew, and P.Y.D. Wong Expression of Cystic Fibrosis Transmembrane Conductance Regulator in Rat Efferent Duct Epithelium Biol Reprod, May 1, 2001; 64(5): 1509 - 1515. [Abstract] [Full Text]
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K. NAKANISHI, W. E. SWEENEY JR., K. MACRAE DELL, C. U. COTTON, and E. D. AVNER Role of CFTR in Autosomal Recessive Polycystic Kidney Disease J. Am. Soc. Nephrol., April 1, 2001; 12(4): 719 - 725. [Abstract] [Full Text] [PDF]
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 J. J. Grantham and J. P. Calvet Polycystic kidney disease: In danger of being X-rated? PNAS, January 30, 2001; 98(3): 790 - 792. [Full Text] [PDF]
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S. González-Perrett, K. Kim, C. Ibarra, A. E. Damiano, E. Zotta, M. Batelli, P. C. Harris, I. L. Reisin, M. A. Arnaout, and H. F. Cantiello Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel PNAS, December 22, 2000; (2000) 21456598. [Abstract] [Full Text]
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A. PERSU, O. DEVUYST, N. LANNOY, R. MATERNE, G. BROSNAHAN, P. A. GABOW, Y. PIRSON, and C. VERELLEN-DUMOULIN CF Gene and Cystic Fibrosis Transmembrane Conductance Regulator Expression in Autosomal Dominant Polycystic Kidney Disease J. Am. Soc. Nephrol., December 1, 2000; 11(12): 2285 - 2296. [Abstract] [Full Text]
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S. H. Low, M. Miura, P. A. Roche, A. C. Valdez, K. E. Mostov, and T. Weimbs Intracellular Redirection of Plasma Membrane Trafficking after Loss of Epithelial Cell Polarity Mol. Biol. Cell, September 1, 2000; 11(9): 3045 - 3060. [Abstract] [Full Text]
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S. M. Huber, G. S. Braun, S. Segerer, R. W. Veh, and M. F. Horster Metanephrogenic mesenchyme-to-epithelium transition induces profound expression changes of ion channels Am J Physiol Renal Physiol, July 1, 2000; 279(1): F65 - F76. [Abstract] [Full Text] [PDF]
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K. HANAOKA and W. B. GUGGINO cAMP Regulates Cell Proliferation and Cyst Formation in Autosomal Polycystic Kidney Disease Cells J. Am. Soc. Nephrol., July 1, 2000; 11(7): 1179 - 1187. [Abstract] [Full Text]
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A. Persu and O. Devuyst Transepithelial chloride secretion and cystogenesis in autosomal dominant polycystic kidney disease Nephrol. Dial. Transplant., June 1, 2000; 15(6): 747 - 750. [Full Text] [PDF]
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K A Lansdell, Z Cai, J F Kidd, and D N Sheppard Two mechanisms of genistein inhibition of cystic fibrosis transmembrane conductance regulator Cl- channels expressed in murine cell line J. Physiol., April 15, 2000; 524(2): 317 - 330. [Abstract] [Full Text] [PDF]
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 N. McCarty Permeation through the CFTR chloride channel J. Exp. Biol., January 7, 2000; 203(13): 1947 - 1962. [Abstract] [PDF]
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P. Upadhya, E. H. Birkenmeier, C. S. Birkenmeier, and J. E. Barker Mutations in a NIMA-related kinase gene, Nek1, cause pleiotropic effects including a progressive polycystic kidney disease in mice PNAS, January 4, 2000; 97(1): 217 - 221. [Abstract] [Full Text] [PDF]
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C. VOGLER, S. HOMAN, A. PUNG, C. THORPE, J. BARKER, E. H. BIRKENMEIER, and P. UPADHYA Clinical and Pathologic Findings in Two New Allelic Murine Models of Polycystic Kidney Disease J. Am. Soc. Nephrol., December 1, 1999; 10(12): 2534 - 2539. [Abstract] [Full Text]
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S. A. Orellana and C. Marfella-Scivittaro Distinctive Cyclic AMP-dependent Protein Kinase Subunit Localization Is Associated with Cyst Formation and Loss of Tubulogenic Capacity in Madin-Darby Canine Kidney Cell Clones J. Biol. Chem., July 7, 2000; 275(28): 21233 - 21240. [Abstract] [Full Text] [PDF]
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D. H. Vandorpe, M. N. Chernova, L. Jiang, L. K. Sellin, S. Wilhelm, A. K. Stuart-Tilley, G. Walz, and S. L. Alper The Cytoplasmic C-terminal Fragment of Polycystin-1 Regulates a Ca2+-permeable Cation Channel J. Biol. Chem., February 2, 2001; 276(6): 4093 - 4101. [Abstract] [Full Text] [PDF]
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S. Gonzalez-Perrett, K. Kim, C. Ibarra, A. E. Damiano, E. Zotta, M. Batelli, P. C. Harris, I. L. Reisin, M. A. Arnaout, and H. F. Cantiello From the Cover: Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel PNAS, January 30, 2001; 98(3): 1182 - 1187. [Abstract] [Full Text] [PDF]
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E. M. Schwiebert, D. P. Wallace, G. M. Braunstein, S. R. King, J. Peti-Peterdi, K. Hanaoka, W. B. Guggino, L. M. Guay-Woodford, P. D. Bell, L. P. Sullivan, et al. Autocrine extracellular purinergic signaling in epithelial cells derived from polycystic kidneys Am J Physiol Renal Physiol, April 1, 2002; 282(4): F763 - F775. [Abstract] [Full Text] [PDF]
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