Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At least two populations of intercalated cells, type A and type B, exist in the connecting tubule (CNT), initial collecting tubule (ICT), and cortical collecting duct (CCD). Type A intercalated cells secrete protons via an apical H+-ATPase and reabsorb bicarbonate by a band 3-like Cl-/HCO3-exchanger, AE1, located in the basolateral plasma membrane. Type B intercalated cells secrete bicarbonate by an apical Cl-/HCO3- exchanger that is distinct from AE1 and remains to be identified. They express H+-ATPase in the basolateral plasma membrane and in vesicles throughout the cytoplasm. A third type of intercalated cell with apical H+-ATPase, but no AE1, has been described in the CNT and CCD of both rat and mouse. The prevalence of the third cell type is not known. The aim of this study was to characterize and quantify intercalated cell subtypes, including the newly described third non A-non B cell, in the CNT, ICT, and CCD of the rat and mouse. A triple immunolabeling procedure was developed in which antibodies to H+-ATPase and band 3 protein were used to identify subpopulations of intercalated cells, and segment-specific antibodies were used to identify distal tubule and collecting duct segments. In both rat and mouse, intercalated cells constituted approximately 40% of the cells in the CNT, ICT, and CCD. Type A, type B, and non A-non B intercalated cells were observed in all of the three segments, with type A cells being the most prevalent in both species. In the mouse, however, non A-non B cells constituted more than half of the intercalated cells in the CNT, 39% in the ICT, and 22% in the CCD, compared with 14, 7, and 5%, respectively, in the rat. In contrast, type B intercalated cells accounted for only 8 to 16% of the intercalated cells in the three segments in the mouse compared with 26 to 39% in the rat. It is concluded that striking differences exist in the prevalence and distribution of the different types of intercalated cells in the CNT, ICT, and CCD of rat and mouse. In the rat, the non A-non B cells are fairly rare, whereas in the mouse, they constitute a major fraction of the intercalated cells, primarily at the expense of the type B intercalated cells.
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PMID:Intercalated cell subtypes in connecting tubule and cortical collecting duct of rat and mouse. 989 Mar 3

In distal renal tubular acidosis (dRTA) the tubular secretion of hydrogen ion in the distal nephron is impaired, leading to the development of metabolic acidosis, frequently accompanied by hypokalemia, nephrocalcinosis, and metabolic bone disease. The condition can be familial, when it is usually inherited as an autosomal dominant, though there is a rarer autosomal recessive form associated with nerve deafness. It has been shown that the autosomal dominant form of dRTA is associated with a defect in the anion exchanger (AE1) of the renal collecting duct intercalated cell. This transporter is a product of the same gene (AE1) as the erythrocyte anion exchanger, band 3. In this review we will look at the evidence for this association. Studies of genomic DNA from families with this disorder have shown, both by genetic linkage studies and by DNA sequencing, that affected individuals are heterozygous for mutations in the AE1 gene whilst unaffected family members have a normal band 3 sequence. Mutations have been found in the region of proposed helices 6 and 7 of the membrane domain of band 3 and involve amino acids Arg-589 and Ser-613, and in the COOH-terminal domain of band 3. Studies of red cell band 3 from these families have provided information on the effect these mutations have on the structure and function of erythrocyte band 3. Expression studies of the erythroid and kidney isoforms of the mutant AE1 proteins, in Xenopus laevis oocytes, have shown that they retained chloride transport activity, suggesting that the disease in the dRTA families is not related simply to the anion transport activity of the mutated proteins. A possible explanation for the dominant effect of these mutant AE1 proteins in the kidney cell is that these mutations affect the targeting of AE1 from the basolateral to the apical membrane of the alpha-intercalated cell.
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PMID:The association between familial distal renal tubular acidosis and mutations in the red cell anion exchanger (band 3, AE1) gene. 1035 4

A mathematical model of the outer medullary collecting duct (OMCD) has been developed, consisting of alpha-intercalated cells and a paracellular pathway, and which includes Na(+), K(+), Cl(-), HCO(3)(-), CO(2), H(2)CO(3), phosphate, ammonia, and urea. Proton secretion across the luminal cell membrane is mediated by both H(+)-ATPase and H-K-ATPase, with fluxes through the H-K-ATPase given by a previously developed kinetic model (Weinstein AM. Am J Physiol Renal Physiol 274: F856-F867, 1998). The flux across each ATPase is substantial, and variation in abundance of either pump can be used to control OMCD proton secretion. In comparison with the H(+)-ATPase, flux through the H-K-ATPase is relatively insensitive to changes in lumen pH, so as luminal acidification proceeds, proton secretion shifts toward this pathway. Peritubular HCO(3)(-) exit is via a conductive pathway and via the Cl(-)/HCO(3)(-) exchanger, AE1. To represent AE1, a kinetic model has been developed based on transport studies obtained at 38 degrees C in red blood cells. (Gasbjerg PK, Knauf PA, and Brahm J. J Gen Physiol 108: 565-575, 1996; Knauf PA, Gasbjerg PK, and Brahm J. J Gen Physiol 108: 577-589, 1996). Model calculations indicate that if all of the chloride entry via AE1 recycles across a peritubular chloride channel and if this channel is anything other than highly selective for chloride, then it should conduct a substantial fraction of the bicarbonate exit. Since both luminal membrane proton pumps are sensitive to small changes in cytosolic pH, variation in density of either AE1 or peritubular anion conductance can modulate OMCD proton secretory rate. With respect to the OMCD in situ, available buffer is predicted to be abundant, including delivered HCO(3)(-) and HPO(4)(2-), as well as peritubular NH(3). Thus, buffer availability is unlikely to exert a regulatory role in total proton secretion by this tubule segment.
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PMID:A mathematical model of the outer medullary collecting duct of the rat. 1089 85

Factors regulating the differentiated phenotype of principal cells (PC) and A- and B-intercalated cells (IC) in kidney collecting ducts are poorly understood. However, we have shown previously that carbonic anhydrase II (CAII)-deficient mice have no IC in their medullary collecting ducts, suggesting a potential role for this enzyme in determining the cellular composition of this tubule segment. We now report that the cellular profile of the collecting ducts of adult rats can be remodeled by inhibiting CA activity in rats by using osmotic pumps containing acetazolamide. The 31-kDa subunit of the vacuolar H(+)-ATPase, the sodium/hydrogen exchanger regulatory factor NHE-RF, and the anion exchanger AE1 were used to identify IC subtypes by immunofluorescence staining, while aquaporin 2 and aquaporin 4 were used to identify PC. In the cortical collecting ducts of animals treated with acetazolamide for 2 wk, the percentage of B-IC decreased significantly (18 +/- 2 vs. 36 +/- 4%, P < 0.01) whereas the percentage of A-IC increased (82 +/- 2 vs. 64 +/- 4%, P < 0.01) with no change in the percentage of total IC in the epithelium. In some treated rats, B-IC were virtually undetectable. In the inner stripe of the outer medulla, the percentage of IC increased in treated animals (48 +/- 2 vs. 37 +/- 3%, P < 0.05) and the percentage of PC decreased (52 +/- 2 vs. 63 +/- 3%, P < 0.05). Moreover, IC appeared bulkier, protruded into the lumen, and showed a significant increase in the length of their apical (20.8 +/- 0.5 vs. 14.6 +/- 0.4 microm, P < 0.05) and basolateral membranes (25.8 +/- 0.4 vs. 23.8 +/- 0.5 microm, P < 0.05) compared with control rats. In the inner medullary collecting ducts of treated animals, the number of IC in the proximal third of the papilla was reduced compared with controls (11 +/- 4 vs. 40 +/- 11 IC/mm(2), P < 0.05). These data suggest that CA activity plays an important role in determining the differentiated phenotype of medullary collecting duct epithelial cells and that the cellular profile of collecting ducts can be remodeled even in adult rats. The relative depletion of cortical B-IC and the relative increase in number and hyperplasia of A-IC in the medulla may be adaptive processes that would tend to correct or stabilize the metabolic acidosis that would otherwise ensue following systemic carbonic anhydrase inhibition.
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PMID:Remodeling the cellular profile of collecting ducts by chronic carbonic anhydrase inhibition. 1118 5

We report 4 distinctive renal epithelial neoplasms that are essentially identical at the morphologic and immunohistochemical levels and do not fit an accepted category in the existing classification of these lesions. The patients were all females, with ages ranging from 32 to 79 years (mean, 50 years). The tumors were well circumscribed and were composed of uniform, predominantly low cuboidal cells with eosinophilic, focally vacuolated cytoplasm. Tumor cells generally formed interconnecting tubules, with smaller areas of cordlike growth and spindling in a bubbly, myxoid stroma. All tumors were confined to the kidney, and all were immunoreactive for high-molecular-weight cytokeratin 34betaE12, cytokeratin 7, epithelial membrane antigen, and cytokeratin cocktail AE1/3. Only 1 tumor was focally immunoreactive for Ulex europaeus agglutinin. Ultrastructural study showed tumor cells forming tubular structures reminiscent of the loop of Henle or distal convoluted tubule. Follow-up in all 4 cases was benign. These distinctive tumors may be confused with aggressive sarcomatoid renal cell carcinomas because of their spindled morphology. The morphologic, immunohistochemical, and ultrastructural features of these lesions indicate differentiation toward distal nephron segments. Similar tumors probably have been reported among low-grade collecting duct carcinomas or tumors "possibly related to the loop of Henle."
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PMID:Low-grade myxoid renal epithelial neoplasms with distal nephron differentiation. 1209 88

Despite chronic acidosis, collecting ducts in adult carbonic anhydrase II-deficient (CAD mice) are depleted of intercalated cells, including those of type A, which are acid-secreting cells. We hypothesized that this depletion could occur during postnatal development. Principal cells were identified by immunofluorescence using an antibody to rat aquaporin-2 (AQP-2), and type A intercalated cells using an antibody specific for anion exchanger (AE1). In CAD mice the proportion of AQP2-positive cells, normal at 11 days, increased progressively in the cortical (CCD) and outer medullary collecting duct (OMCD), to reach almost 100% in the OMCD in adults. The percentage of AE1-positive cells in the OMCD of CAD mice decreased by half by 6 weeks of age and further by adulthood. In controls, however, the proportion of AQP2-positive cells and that of AE1-positive cells in the OMCD remained stable after 10 days of age. AE1-positive cells accounted for the majority of intercalated cells in the OMCD. The mechanisms leading to selective postnatal cell depletion in the collecting duct in CAD mice remain to be determined.
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PMID:Postnatal disappearance of type A intercalated cells in carbonic anhydrase II-deficient mice. 1142 Sep 10

The rabbit kidney possesses mRNA for the H-K-ATPase alpha(1)-subunit (HKalpha(1)) and two splice variants of the H-K-ATPase alpha(2)-subunit (HKalpha(2)). The purpose of this study was to determine the specific distribution of one of these, the H-K-ATPase alpha(2c)-subunit isoform (HKalpha(2c)), in rabbit kidney by immunohistochemistry. Chicken polyclonal antibodies against a peptide based on the NH(2) terminus of HKalpha(2c) were used to detect HKalpha(2c) immunoreactivity in tissue sections. Immunohistochemical localization of HKalpha(2c) revealed intense apical immunoreactivity in a subpopulation of cells in the connecting segment, cortical collecting duct, and outer medullary collecting duct in both the outer and inner stripe. An additional population of cells exhibited a thin apical band of immunolabel. Immunohistochemical colocalization of HKalpha(2c) with carbonic anhydrase II, the Cl(-)/HCO exchanger AE1, and HKalpha(1) indicated that both type A and type B intercalated cells possessed intense apical HKalpha(2c) immunoreactivity, whereas principal cells and connecting segment cells had only a thin apical band of HKalpha(2c). Labeled cells were evident through the middle third of the inner medullary collecting duct in the majority of animals. Immunolabel was also present in papillary surface epithelial cells, cells in the cortical thick ascending limb of Henle's loop (cTAL), and the macula densa. Thus in the rabbit kidney, apical HKalpha(2c) is present and may contribute to acid secretion or potassium uptake throughout the connecting segment and collecting duct in both type A and type B intercalated cells, principal cells, and connecting segment cells, as well as in cells in papillary surface epithelium, cTAL, and macula densa.
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PMID:Immunohistochemical localization of H-K-ATPase alpha(2c)-subunit in rabbit kidney. 1145 28

Genetic disorders of acid-base transporters involve plasmalemmal and organellar transporters of H(+), HCO3(-), and Cl(-). Autosomal-dominant and -recessive forms of distal renal tubular acidosis (dRTA) are caused by mutations in ion transporters of the acid-secreting Type A intercalated cell of the renal collecting duct. These include the AE1 Cl(-)/HCO3(-) exchanger of the basolateral membrane and at least two subunits of the apical membrane vacuolar (v)H(+)-ATPase, the V1 subunit B1 (associated with deafness) and the V0 subunit a4. Recessive proximal RTA with ocular disease arises from mutations in the electrogenic Na(+)-bicarbonate cotransporter NBC1 of the proximal tubular cell basolateral membrane. Recessive mixed proximal-distal RTA accompanied by osteopetrosis and mental retardation is associated with mutations in cytoplasmic carbonic anhydrase II. The metabolic alkalosis of congenital chloride-losing diarrhea is caused by mutations in the DRA Cl(-)/HCO3(-) exchanger of the ileocolonic apical membrane. Recessive osteopetrosis is caused by deficient osteoclast acid secretion across the ruffled border lacunar membrane, the result of mutations in the vH(+)-ATPase V0 subunit or in the CLC-7 Cl(-) channel. X-linked nephrolithiasis and engineered deficiencies in some other CLC Cl(-) channels are thought to represent defects of organellar acidification. Study of acid-base transport disease-associated mutations should enhance our understanding of protein structure-function relationships and their impact on the physiology of cell, tissue, and organism.
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PMID:Genetic diseases of acid-base transporters. 1182 92

Regulation of cell pH and cell volume require homeostatic control of intracellular cations and anions. Bicarbonate transporters play an important role in these cellular functions. The SLC4 and SLC26 gene families both encode bicarbonate transporter polypeptides. The SLC4 gene family includes four Na+-independent chloride-bicarbonate exchanger genes and multiple Na+-bicarbonate cotransporter and Na+-dependent anion-exchanger genes. The acute regulatory properties of the recombinant polypeptides encoded by these genes remain little studied. The most extensively studied among them are the Na+-independent anion exchangers AE1, AE2, and AE3. The widely expressed AE2 anion exchanger participates in recovery from alkaline load and in regulatory cell volume increase following shrinkage. AE2 can also be regulated by the ammonium ion. These properties are not shared by the closely related AE1 anion exchanger of the erythrocyte and the renal collecting duct Type A intercalated cell. Structure-function studies of recombinant proteins involving chimeras, deletions, and point mutations have delineated regions of AE2, which are important in the exhibition of the regulatory properties absent from AE1. These include regions of the transmembrane domain and the N-terminal cytoplasmic domain. Noncontiguous regions in the middle of the N-terminal cytoplasmic domain are of particular importance for acute regulation by several types of stimulus.
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PMID:How pH regulates a pH regulator: a regulatory hot spot in the N-terminal cytoplasmic domain of the AE2 anion exchanger. 1213 98

The outer medullary collecting duct (OMCD) plays an important role in mediating transepithelial HCO transport [J(HCO(3)(-))] and urinary acidification. HCO absorption by type A intercalated cells in the OMCD inner stripe (OMCD(is)) segment is thought to by mediated by an apical vacuolar H(+)-ATPase and H(+)-K(+)-ATPase coupled to a basolateral Cl(-)-HCO exchanger (AE1). Besides these Na(+)-independent transporters, previous studies have shown that OMCD(is) type A intercalated cells have an apical electroneutral EIPA-sensitive, DIDS-insensitive Na(+)-HCO cotransporter (NBC3); a basolateral Na(+)/H(+) antiporter; and a basolateral Na(+)-K(+)-ATPase. In this study, we reexamined the Na(+) dependence of transepithelial Na(+) transport in the OMCD(is) and determined the role of apical NBC3 in intracellular (pH(i)) regulation in OMCD(is) type A intercalated cells. Control tubules absorbed HCO at a rate of approximately 13 pmol. min(-1). mm(-1). Lowering luminal Na(+) from 140 to 40 mM decreased [J(HCO(3)(-))] by approximately 15% without a change in transepithelial potential (V(te)). Furthermore, 50 microM EIPA (lumen) also decreased [J(HCO(3)(-))] by approximately 13% without a change in V(te). The effect of lowering luminal Na(+) and adding EIPA were not additive. These results demonstrate that [J(HCO(3)(-))] in the OMCD(is) is in part Na(+) dependent. In separate experiments, the pH(i) recovery rate after an NH prepulse was monitored in single type A intercalated cells with confocal fluorescence microscopy. The pH(i) recovery rate was approximately 0.21 pH/min in Na(+)-containing solutions and decreased to approximately 0.16 pH/min with EIPA (50 microM, lumen). In tubules perfused/bathed without Na(+), luminal Na(+) addition resulted in a pH(i) recovery rate of approximately 0.36 pH/min, whereas the Na(+)-independent recovery rate was approximately 0.16 pH/min. EIPA (50 microM, lumen) decreased the Na(+)-dependent pH(i) recovery rate to approximately 0.07 pH/min. The Na(+)-independent recovery rate was decreased to approximately 0.06 pH/min by bafilomycin (10 nM, lumen) and to approximately 0.10 pH/min using Schering 28080 (10 microM, lumen). These findings indicate that NBC3 contributes to pH(i) regulation in OMCD(is) type A intercalated cells and plays only a minor role in mediating [J(HCO(3)(-))] in the OMCD(is).
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PMID:Apical H(+)/base transporters mediating bicarbonate absorption and pH(i) regulation in the OMCD. 1237 86


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