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Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The collecting duct is responsible for the final secretion or reabsorption of protons and bicarbonate, respectively. Approximately 2% of the total filtered bicarbonate is reabsorbed in this segment. At least two different types of cells are involved in the transport of protons and bicarbonate, namely, type A and B intercalated cells. Their relative abundance differs in zonal distribution in the collecting duct. A variety of transport proteins and enzymes take part in the transcellular movement of protons and bicarbonate, some of them identified on a molecular level. These proteins are tightly regulated by hormones such as angiotensin II, aldosterone or endothelin or by the metabolic status of the organism. Alterations in acid-base intake or electrolyte status have profound effects on the collecting duct. Moreover, drugs interacting with renal electrolyte or bicarbonate handling (i.e. diuretics, glucocorticoids) also often affect acid-base transport in the collecting duct. For some of the identified proteins mutations have been found in various genetic diseases and syndromes of distal renal tubular acidosis leading to metabolic acidosis and an increased risk of nephrocalcinosis or -lithiasis.
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PMID:Acid-base transport in the collecting duct. 1202 10

A mathematical model of the rat collecting duct (CD) has been developed by concatenating previously published models of cortical (Weinstein AM. Am J Physiol Renal Physiol 280: F1072-F1092, 2001); outer medullary (Weinstein AM. Am J Physiol Renal Physiol 279: F24-F45, 2000); and inner medullary segments (Weinstein AM. Am J Physiol Renal Physiol 274: F841-F855, 1998). Starting with end-distal tubular flow rate and composition, plus interstitial solute profiles, the model predicts urinary solute flows, including the buffer concentrations required to assess net acid excretion. In the model CD, the interstitial corticomedullary osmotic gradient provides the basis for the flow effect on the transport of several solutes. For substances that have an interstitial accumulation and that can have diffusive secretion (e.g., urea and NH(4)(+)), enhanced luminal flow increases excretion by decreasing luminal accumulation. For substances that are reabsorbed (e.g., K+ and HCO(3)(-)), and for which luminal accumulation can enhance reabsorption, increasing luminal flow again increases excretion by decreasing luminal solute concentration. In model calculations, flow-dependent increases in HCO(3)(-) and NH(4)(+) approximately balance, so net acid excretion is little changed by flow, albeit at a higher urinary pH. The model identifies delivery flow rate to the CD as a potent determinant of urinary pH, with high flows blunting maximal acidification. At even modestly high flows (9 nl x min-1. tubule-1, with 6% of filtered Na+ entering the CD), the model cannot achieve a urinary pH <5.5 unless the delivered HCO(3)(-) concentration is extremely low (<2 mM). Nevertheless, simulation of Na2SO4 diuresis does yield both an increase in net acid excretion and a decrease in urinary HCO(3)(-) (i.e., a decrease in pH) despite the increase in urinary flow. This model should provide a tool for examining hypotheses regarding transport defects underlying distal renal tubular acidosis.
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PMID:A mathematical model of rat collecting duct. I. Flow effects on transport and urinary acidification. 1238 78

A mathematical model of the rat collecting duct (CD) is used to examine the effect of delivered load of bicarbonate and nonbicarbonate buffer on urinary acidification. Increasing the delivered load of HCO(3)(-) produces bicarbonaturia, and, with luminal carbonic anhydrase absent, induces a disequilibrium luminal pH and a postequilibration increase in urinary PCO2. At baseline flows, this disequilibrium disappears when luminal carbonic anhydrase rate coefficients reach 1% of full catalysis. The magnitude of the equilibration PCO2 depends on the product of urinary acid phosphate concentration and the disequilibrium pH. Thus, although increasing phosphate delivery to the CD decreases the disequilibrium pH, the increase in urinary phosphate concentration yields an overall increase in postequilibration PCO2. In simulations of experimental HCO(3)(-) loading in the rat, model predictions of urinary PCO2 exceed the measured PCO2 of bladder urine. In part, the higher model predictions for urinary PCO2 may reflect higher urinary flow rates and lower urinary phosphate concentrations in the experimental preparations. However, when simulation of CD function during HCO(3)(-) loading acknowledges the high ambient renal medullary PCO2 (5), the predicted urinary PCO2 of the model CD is yet that much greater. This discrepancy cannot be resolved within the model but requires additional experimental data, namely, concomitant determination of urinary buffer concentrations within the tubule fluid sampled for PCO2 and pH. This model should provide a means for simulating formal testing of urinary acidification and thus for examining hypotheses regarding transport defects underlying distal renal tubular acidosis.
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PMID:A mathematical model of rat collecting duct. II. Effect of buffer delivery on urinary acidification. 1238 79

The present clinical taxonomy of distal renal tubular acidoses includes "gradient," "secretory," and "voltage" defects. These categories refer to presumed collecting duct defects in which the epithelium may be abnormally permeable and unable to sustain an ion gradient, in which luminal proton ATPases are defective, or in which electrogenic Na+ reabsorption is impaired and luminal electronegativity is reduced. Classification of affected individuals is based on urinary pH and ion concentrations during spontaneous acidosis and during SO(4)(2-) infusion, as well as urinary PCO2 during HCO(3)(-) loading. A model of rat CD has been developed that has been used to examine determinants of urinary acidification (Weinstein AM. Am J Physiol Renal Physiol 283: F1252-F1266, 2002) and the interplay of HCO(3)(-) and PO(4)(3-) loads to generate a disequlibrium pH and equilibrium PCO2. In this paper, pure forms of gradient, voltage, and secretory defects are simulated, with attention to variability in the locus of the defect in the cortical (CCD), outer medullary (OMCD), or inner medullary collecting duct (IMCD). The objective of these calculations is to discover whether the intuitive description of these defects is sustained quantitatively. The most important positive finding is that the locus of the transport defect along the CD plays a critical role in the apparent severity of the lesion, with more proximal defects being less severe and more easily correctable. In particular, model calculations suggest that for gradient or secretory defects to be clinically detectable they need to involve the OMCD and/or IMCD. Additionally, the calculations reveal a possible mechanism for CD K+ wasting, which does not involve failure of H+ - K+-ATPase but derives from a paracellular anion leak and thereby a more electronegative lumen. The most important negative finding is the lack of support for the category of renal tubular acidosis associated with a voltage defect. Although CD lesions that present with both K+ and H+ secretory defects suggest mediation by transepithelial electrical potential difference (PD), both PD changes and proton pump PD sensitivity appear too small to account for the observed abnormalities.
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PMID:A mathematical model of rat collecting duct. III. Paradigms for distal acidification defects. 1238 80

A large proportion of autosomal recessive distal renal tubular acidosis (RTA) is associated with mutations in the ATP6B1 gene encoding the B1 subunit of H+-ATPase. H+-ATPase is one of the key membrane transporters for net acid excretion in the alpha-intercalated cells of the medullary collecting duct. Sensorineural hearing loss frequently accompanies this type of distal RTA. Mutational analysis of the ATP6B1 gene in a 9-year-old Korean boy with distal RTA and sensorineural hearing loss found 2 heterozygous missense point mutations. Although a single case report, this is the second report documenting ATP6B1 mutations in recessive distal RTA with sensorineural hearing loss after the original report by Karet et al and confirms the novelty of these mutations.
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PMID:ATP6B1 gene mutations associated with distal renal tubular acidosis and deafness in a child. 1250 Feb 43

The multisubunit vacuolar-type proton-translocating ATPases (H(+)-ATPases) mediate the acidification of various intracellular organelles. In a subset of tissues, they also mediate H(+) secretion at the plasma membrane. Two isoforms of the H(+)-ATPase B-subunit exist in humans; we have shown that mutations in ATP6V1B1, encoding the B1-isoform, cause the clinical condition distal renal tubular acidosis. Here we report the cloning and characterization of murine Atp6v1b1, which encodes a 513-amino acid (aa) protein with 93% identity to human ATP6V1B1. Genomic organization is conserved between the murine and human H(+)-ATPase B1-subunits, and Atp6v1b1 maps to a region of mouse chromosome 6 syntenic to human 2p13, the location of ATP6V1B1. Northern blotting detects a 2.2-kb Atp6v1b1 transcript in the kidney and testis, but not other major organs. In mouse kidney, the B1-subunit localizes to intercalated cells of the cortical and medullary collecting duct. B1 protein levels were not increased in either mouse renal cortex or medulla after either 2 or 7 days of oral acid loading. These results demonstrate that Atp6v1b1 encodes the murine ortholog of human ATP6V1B1 and provides a tool for future development of animal models based on manipulation of the Atp6v1b1 genomic locus.
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PMID:Molecular cloning and characterization of Atp6v1b1, the murine vacuolar H+ -ATPase B1-subunit. 1458 95

Vacuolar-type H(+)-ATPases (V-H(+)-ATPases) are the major H(+)-secreting protein in the distal portion of the nephron and are involved in net H(+) secretion (bicarbonate generation) or H(+) reabsorption (net bicarbonate secretion). In addition, V-H(+)-ATPases are involved in HCO(3)(-) reabsorption in the proximal tubule and distal tubule. V-H(+)-ATPases consist of at least 13 subunits, the functions of which have not all been elucidated. Mutations in the accessory ATP6V0A4 (a4 isoform) subunit have recently been shown to cause an inherited form of distal renal tubular acidosis in humans. Here, the localization of this subunit in human and mouse kidney was studied and the regulation of expression and localization of this subunit in mouse kidney in response to acid-base and electrolyte intake was investigated. Reverse transcription-PCR on dissected mouse nephron segments amplified a4-specific transcripts in proximal tubule, loop of Henle, distal convoluted tubule, and cortical and medullary collecting duct. a4 protein was localized by immunohistochemistry to the apical compartment of the proximal tubule (S1/S2 segment), the loop of Henle, the intercalated cells of the distal convoluted tubule, the connecting segment, and all intercalated cells of the entire collecting duct in human and mouse kidney. All types of intercalated cells expressed a4. NH(4)Cl or NaHCO(3) loading for 24 h, 48 h, or 7 d as well as K(+) depletion for 7 and 14 d had no influence on a4 protein expression levels in either cortex or medulla as determined by Western blotting. Immunohistochemistry, however, demonstrated a subcellular redistribution of a4 in response to the different stimuli. NH(4)Cl and K(+) depletion led to a pronounced apical staining in the connecting segment, cortical collecting duct, and outer medullary collecting duct, whereas NaHCO(3) loading caused a stronger bipolar staining in the cortical collecting duct. Taken together, these results demonstrate a4 expression in the proximal tubule, loop of Henle, distal tubule, and collecting duct and suggest that under conditions in which increased V-H(+)-ATPase activity is required, a4 is regulated by trafficking but not protein expression. This may allow for the rapid adaptation of V-H(+)-ATPase activity to altered acid-base intake to achieve systemic pH homeostasis. The significance of a4 expression in the proximal tubule in the context of distal renal tubular acidosis will require further clarification.
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PMID:Localization and regulation of the ATP6V0A4 (a4) vacuolar H+-ATPase subunit defective in an inherited form of distal renal tubular acidosis. 1463 2

The collecting ducts of the kidney are composed of intercalated cells (responsible for acid/base transport), principal cells (mediating salt and water absorption), and inner medullary cells, which mediate all three types of transport. Forkhead box (Fox) genes are a large family of transcription factors that are important in cell-type specification during organogenesis. In this issue, Blomqvist et al. find that mice lacking Foxi1 have no intercalated cells in the kidney. The collecting ducts of the null mice contained primitive cells that expressed both intercalated cell and principal cell proteins, yet the acid/base transport function of the kidney was disrupted and the mice exhibited distal renal tubular acidosis. These findings suggest that Foxi1 plays a critical role in determining cell identity during collecting duct development.
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PMID:A fork in the road of cell differentiation in the kidney tubule. 1517 82

Intercalated cells are highly specialized cells within the renal collecting duct epithelium and play an important role in systemic acid-base homoeostasis. Whereas type A intercalated cells secrete protons via an apically localized H+-ATPase, type B intercalated cells secrete HCO3-. Type B intercalated cells specifically express the HCO3-/Cl- exchanger AE4 (anion exchanger 4), encoded by Slc4a9. Mice with a targeted disruption of the gene for the forkhead transcription factor Foxi1 display renal tubular acidosis due to an intercalated cell-differentiation defect. Collecting duct cells in these mice are characterized by the absence of inter-calated cell markers including AE4. To test whether Slc4a9 is a direct target gene of Foxi1, an AE4 promoter construct was generated for a cell-based reporter gene assay. Co-transfection with the Foxi1 cDNA resulted in an approx. 100-fold activation of the AE4 promoter construct. By truncating the AE4 promoter at the 5'-end, we demonstrate that a fragment of approx. 462 bp upstream of the transcription start point is sufficient to mediate activation by Foxi1. Sequence analysis of this region revealed at least eight potential binding sites for Foxi1 in both sense and antisense orientation. Only one element was bound by recombinant Foxi1 protein in bandshift assays. Mutation of this site abolished both binding in bandshift assays and transcriptional activation by co-transfection of Foxi1 in the reporter gene assay. We thus identify the AE4 promoter as a direct target of Foxi1.
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PMID:The forkhead transcription factor Foxi1 directly activates the AE4 promoter. 1615 12

The multisubunit vacuolar-type H(+)ATPases mediate acidification of various intracellular organelles and in some tissues mediate H(+) secretion across the plasma membrane. Mutations in the B1-subunit of the apical H(+)ATPase that secretes protons in the distal nephron cause distal renal tubular acidosis in humans, a condition characterized by metabolic acidosis with an inappropriately alkaline urine. To examine the detailed cellular and organismal physiology resulting from this mutation, we have generated mice deficient in the B1-subunit (Atp6v1b1(-/-) mice). Urine pH is more alkaline and metabolic acidosis is more severe in Atp6v1b1(-/-) mice after oral acid challenge, demonstrating a failure of normal urinary acidification. In Atp6v1b1(-/-) mice, the normal urinary acidification induced by a lumen-negative potential in response to furosemide infusion is abolished. After an acute intracellular acidification, Na(+)-independent pH recovery rates of individual Atp6v1b1(-/-) intercalated cells of the cortical collecting duct are markedly reduced and show no further decrease after treatment with the selective H(+)ATPase inhibitor concanamycin. Apical expression of the alternative B-subunit isoform, B2, is increased in Atp6v1b1(-/-) medulla and colocalizes with the H(+)ATPase E-subunit; however, the greater severity of metabolic acidosis in Atp6v1b1(-/-) mice after oral acid challenge indicates that the B2-subunit cannot fully functionally compensate for the loss of B1. Our results indicate that the B1 isoform is the major B-subunit isoform that incorporates into functional, plasma membrane H(+)ATPases in intercalated cells of the cortical collecting duct and is required for maximal urinary acidification.
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PMID:The B1-subunit of the H(+) ATPase is required for maximal urinary acidification. 1617 50


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