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)

An electroneutral thiazide-sensitive Na-Cl cotransport pathway (TSC) has been localized functionally to the distal convoluted tubule (DCT), although the TSC has also been detected in the connecting tubule (CNT), the cortical collecting duct, and the medullary collecting tubule as well. The present experiments were designed to localize expression of message for the TSC in rat and human kidney. A riboprobe, generated from the mouse TSC, was used for in situ hybridization. Simultaneous immunocytochemistry, using antibodies to Tamm-Horsfall protein, band 3, and the Na+/Ca2+ exchanger, permitted delineation of specific nephron segments. In rat, message for the TSC was highly expressed in DCT cells but not elsewhere. The transition from thick ascending limb to DCT was abrupt, whereas the transition to CNT was gradual. In the more distal region of rat DCT (DCT-2), which contained few intercalated cells, both TSC message and Na+/Ca2+ exchanger immunoreactivity were present. Treatment of rats with furosemide for 5 days increased expression of TSC message within the DCT but did not induce its expression elsewhere. In humans, expression of TSC message was also highest in cells of the DCT. In humans, however, expression extended well into the CNT. These experiments indicate that the TSC is expressed predominantly by DCT cells in both rat and humans, although expression extends into the CNT cells in humans. They also show that the TSC and Na+/Ca2+ exchanger are coexpressed by a subpopulation of DCT cells near the junction with the CNT.
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PMID:Expression of the thiazide-sensitive Na-Cl cotransporter in rat and human kidney. 859 86

Mineralocorticoid hormones regulate salt transport along the distal nephron by binding to intracellular receptors and activating gene transcription. Previous experiments showed that systemic aldosterone infusions stimulate thiazide-sensitive Na and Cl transport by distal convoluted tubule (DCT) cells; this effect could have been direct or secondary to systemic hormonal effects. Aldosterone target tissues express both mineralocorticoid receptors and the metabolic enzyme 11beta-hydroxysteroid dehydrogenase type 2. Mineralocorticoid receptors have been localized to the DCT in some experiments, but not in others. Expression of 11beta-hydroxysteroid dehydrogenase type 2 by DCT cells has not been investigated. The present experiments were designed to test the hypothesis that rat DCT cells are targets of aldosterone action. Patterns of mineralocorticoid receptor, 11beta-hydroxysteroid dehydrogenase, thiazide-sensitive Na-Cl cotransporter, and Na/Ca exchanger expression along the distal tubule were examined. A polyclonal antibody was generated to localize the thiazide-sensitive Na-Cl cotransporter. Thiazide-sensitive Na-Cl cotransporter and 11beta-hydroxysteroid dehydrogenase expression were examined using both in situ hybridization and immunocytochemistry; Na/Ca exchanger and mineralocorticoid receptor expression were examined by immunocytochemistry. The results indicate that 11beta-hydroxysteroid dehydrogenase is expressed by DCT cells, as well as connecting tubule cells and principal cells of the collecting duct; expression levels are low near the junction with the thick ascending limb and rise near the transition to the connecting tubule. Mineralocorticoid receptors are expressed by DCT cells, as well as along the thick ascending limb, connecting tubule, and collecting duct. The results indicate that components of the mineralocorticoid receptor system are expressed by DCT cells, suggesting that these cells are targets of aldosterone action.
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PMID:11Beta-hydroxysteroid dehydrogenase, mineralocorticoid receptor, and thiazide-sensitive Na-Cl cotransporter expression by distal tubules. 969 56

Although the collecting duct is regarded as the primary site at which mineralocorticoids regulate renal sodium transport in the kidney, recent evidence points to the distal convoluted tubule as a possible site of mineralocorticoid action. To investigate whether mineralocorticoids regulate the expression of the thiazide-sensitive Na-Cl cotransporter (TSC), the chief apical sodium entry pathway of distal convoluted tubule cells, we prepared an affinity-purified, peptide-directed antibody to TSC. On immunoblots, the antibody recognized a prominent 165-kDa band in membrane fractions from the renal cortex but not from the renal medulla. Immunofluorescence immunocytochemistry showed TSC labeling only in distal convoluted tubule cells. Semiquantitative immunoblotting studies demonstrated a large increase in TSC expression in the renal cortex of rats on a low-NaCl diet (207 +/- 21% of control diet). Immunofluorescence localization in tissue sections confirmed the strong increase in TSC expression. Treatment of rats for 10 days with a continuous subcutaneous infusion of aldosterone also increased TSC expression (380 +/- 58% of controls). Furthermore, 7-day treatment of rats with an orally administered mineralocorticoid, fludrocortisone, increased TSC expression (656 +/- 114% of controls). We conclude that the distal convoluted tubule is an important site of action of the mineralocorticoid aldosterone, which strongly up-regulates the expression of TSC.
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PMID:The thiazide-sensitive Na-Cl cotransporter is an aldosterone-induced protein. 982 38

The currently available diuretics increase the urinary excretion of sodium chloride by selective inhibition of specific sodium transporters in the loop of Henle and distal nephron. In recent years, the molecular cloning of the distal diuretic-sensitive sodium transporters has improved our understanding of the cellular mechanisms of action of each class of diuretics. The identification of mutations in the genes encoding these transporters in inherited disorders characterized by altered salt balance has provided unequivocal evidence for the roles of the cloned diuretic-sensitive transporters in sodium homeostasis. The biochemical abnormalities observed in these disorders are identical to those induced by the specific diuretic. In the Guibaud-Vainsel syndrome (renal-tubular acidosis with osteopetrosis) the renal disturbances are comparable to the effects of a therapy with acetazolamide. Mutations in the proximal tubular carbonic anhydrase type II are the cause of this rare disorder. Bartter syndrome shows identical biochemical abnormalities as those found with chronic furosemide therapy. This syndrome is caused by mutations in the furosemide-sensitive Na-K-2Cl cotransporter in the thick ascending loop of Henle. In Gitelman syndrome the characteristic electrolyte and hormonal changes in blood and urine are comparable to those observed in patients treated with thiazide diuretics. This disorder results from mutations in the distal-tubular thiazide-sensitive Na-Cl cotransporter. The two forms of pseudhypoaldosteronism are distinguished by the characteristic metabolic changes encountered with a therapy with potassium-sparing diuretics. The genetic disturbance resides either in the amiloride-sensitive epithelial sodium channel (autosomal-dominant form) or in the spironolactone-sensitive mineralocorticoid receptor (autosomal-recessive form) in the distal tubule and cortical collecting duct. Current research concentrates on defining the structural sites for electrolyte transport and diuretic binding, as well as the molecular mechanisms of transport regulation. This information may allow a more appropriate use of diuretics and the design of new substances with diuretic action.
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PMID:[Pharmacologic action of diuretics in the kidney]. 1089 17

Increased systemic acid intake is associated with an increase in apical Na/H exchange in the renal proximal tubule mediated by the type 3 Na/H exchanger (NHE3). Because NHE3 mediates both proton secretion and Na absorption, increased NHE3 activity could inappropriately perturb Na balance unless there are compensatory changes in Na handling. In this study, we use semiquantitative immunoblotting of rat kidneys to investigate whether acid loading is associated with compensatory decreases in the abundance of renal tubule Na transporters other than NHE3. Long-term (i.e., 7-day) acid loading with NH(4)Cl produced large decreases in the abundances of the thiazide-sensitive Na-Cl cotransporter (TSC/NCC) of the distal convoluted tubule and both the beta- and gamma-subunits of the amiloride-sensitive epithelial Na channel (ENaC) of the collecting duct. In addition, the renal cortical abundance of the proximal type 2 Na-dependent phosphate transporter (NaPi-2) was markedly decreased. In contrast, abundances of the bumetanide-sensitive Na-K-2Cl cotransporter of the thick ascending limb and the alpha-subunit of ENaC were unchanged. A similar profile of changes was seen with short-term (16-h) acid loading. Long-term (7-day) base loading with NaHCO(3) resulted in the opposite pattern of response with marked increases in the abundances of the beta- and gamma-subunits of ENaC and NaPi-2. These adaptations may play critical roles in the maintenance in Na balance when changes in acid-base balance occur.
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PMID:Long-term regulation of renal Na-dependent cotransporters and ENaC: response to altered acid-base intake. 1096 25

Previous studies have established that the vasopressin-regulated water channel of the collecting duct, aquaporin-2, is excreted in the urine, providing a means for assessment of regulation and dysregulation of aquaporin-2 in humans. This article addresses the hypothesis that membrane transporters from upstream nephron segments are normally detectable in urine. The experiments employed rabbit polyclonal antibodies against the major Na transporters of the proximal tubule (the type 3 Na-H exchanger [NHE3]), the thick ascending limb of Henle's loop (the bumetanide-sensitive Na-K-2Cl cotransporter [NKCC2]), and the distal convoluted tubule (the thiazide-sensitive Na-Cl cotransporter [NCC]) in immunoblotting experiments. All three of these transporters were readily detectable as high molecular weight complexes present in lowdensity membrane fractions from urine of normal rats. Cross linking studies of NHE3, NKCC2, and NCC revealed that high molecular weight complexes are normally present in renal tissue. The molecular weights of the complexes in urine matched those of the cross-linked complexes in native kidney tissue. The presence in urine of integral membrane proteins representative of each nephron segment raises the possibility that limited or comprehensive proteomic analysis of urine samples may be useful in clinical settings.
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PMID:Detection of Na(+) transporter proteins in urine. 1105 90

Hyponatremia is associated with inappropriately elevated vasopressin levels. A brisk natriuresis precedes the escape from this antidiuresis. Thus, the hypothesis was that the abundance of one or more of the sodium transporters of the distal tubule (a site for fine tuning of sodium balance) would be altered during vasopressin escape. Semiquantitative immunoblotting was used to examine the regulation of abundance of several sodium transporters/channels of the thick ascending limb through the collecting duct in the rat model. Osmotic minipumps to infuse dDAVP, the V2-selective vasopressin agonist (5 ng/h) for the entire experiment, were implanted in Male Sprague-Dawley rats. After 4 d, rats were divided into a control (dry AIN-76 diet/ad libitum water) or a water-loaded (gelled-agar-AIN-76 diet/ad libitum water) group. Rats were killed after 1, 2, 3, or 7 additional days. The water-loaded rats were hyponatremic (plasma Na+, 98 to 122 mmol/L) and manifested the expected early natriuresis and diuresis of vasopressin escape. Water loading (with dDAVP infusion) resulted in increased whole-kidney abundances of the thiazide-sensitive Na-Cl co-transporter, the alpha-subunit of the epithelial sodium channel (ENaC), and the 70-kD dimer of the gamma-subunit of ENaC. No changes were observed for the ss-subunit of ENaC. Similar protein changes have recently been associated with elevated aldosterone levels in rats. However, plasma aldosterone levels were significantly suppressed in this model. These data suggest that several distal sodium reabsorptive mechanisms are upregulated during vasopressin escape; this may help to attenuate the developing hyponatremia resulting from water loading when vasopressin levels are inappropriately elevated.
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PMID:Increased abundance of distal sodium transporters in rat kidney during vasopressin escape. 1115 10

Diabetes mellitus (DM) is associated with osmotic diuresis and natriuresis. At day 15, rats with DM induced by streptozotocin (n = 13) had severe hyperglycemia (27.1 +/- 0.4 vs. 4.7 +/- 0.1 mM in controls) and had a fivefold increase in water intake (123 +/- 5 vs. 25 +/- 2 ml/day) and urine output. Semiquantitative immunoblotting revealed a significant increase in inner medullary AQP2 (201 +/- 12% of control rats, P < 0.05) and phosphorylated (Ser(256)) AQP2 (p-AQP2) abundance (299 +/- 32%) in DM rats. Also, the abundance of inner medullary AQP3 was markedly increased to 171 +/- 19% of control levels (100 +/- 4%, n = 7, P < 0.05). In contrast, the abundance of whole kidney AQP1 (90 +/- 3%) and inner medullary AQP4 (121 +/- 16%) was unchanged in rats with DM. Immunoelectron microscopy further revealed an increased labeling of AQP2 in the apical plasma membrane of collecting duct principal cells (with less labeling in the intracellular vesicles) of DM rats, indicating enhanced trafficking of AQP2 to the apical plasma membrane. There was a marked increase in urinary sodium excretion in DM. Only Na(+)/H(+) exchanger NHE3 was downregulated (67 +/- 10 vs. 100 +/- 11%) whereas there were no significant changes in abundance of type 2 Na-phosphate cotransporter (128 +/- 6 vs. 100 +/- 10%); the Na-K-2Cl cotransporter (125 +/- 19 vs. 100 +/- 10%); the thiazide-sensitive Na-Cl cotransporter (121 +/- 9 vs. 100 +/- 10%); the alpha(1)-subunit of the Na-K-ATPase (106 +/- 7 vs. 100 +/- 5%); and the proximal tubule Na-HCO(3) cotransporter (98 +/- 16 vs. 100 +/- 7%). In conclusion, DM rats had an increased AQP2, p-AQP2, and AQP3 abundance as well as high AQP2 labeling of the apical plasma membrane, which is likely to represent a vasopressin-mediated compensatory increase in response to the severe polyuria. In contrast, there were no major changes in the abundance of AQP1, AQP4, and several major proximal and distal tubule Na(+) transporters except NHE3 downregulation, which may participate in the increased sodium excretion.
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PMID:Compensatory increase in AQP2, p-AQP2, and AQP3 expression in rats with diabetes mellitus. 1124 63

Nifedipine, a calcium antagonist, has diuretic and natriuretic properties. However, the molecular mechanisms by which these effects are produced are poorly understood. We examined kidney abundance of aquaporins (AQP1, AQP2, and AQP3) and major sodium transporters [type 3 Na/H exchanger (NHE-3); type 2 Na-Pi cotransporter (NaPi-2); Na-K-ATPase; type 1 bumetanide-sensitive cotransporter (BSC-1); and thiazide-sensitive Na-Cl cotransporter (TSC)] as well as inner medullary abundance of AQP2, phosphorylated-AQP2 (p-AQP2), AQP3, and calcium-sensing receptor (CaR). Rats treated with nifedipine orally (700 mg/kg) for 19 days had a significant increase in urine output, whereas urinary osmolality and solute-free water reabsorption were markedly reduced. Consistent with this, immunoblotting revealed a significant decrease in the abundance of whole kidney AQP2 (47 +/- 7% of control rats, P < 0.05) and in inner medullary AQP2 (60 +/- 7%) as well as in p-AQP2 abundance (17 +/- 6%) in nifedipine-treated rats. In contrast, whole kidney AQP3 abundance was significantly increased (219 +/- 28%). Of potential importance in modulating AQP2 levels, the abundance of CaR in the inner medulla was significantly increased (295 +/- 25%) in nifedipine-treated rats. Nifedipine treatment was also associated with increased urinary sodium excretion. Consistent with this, semiquantitative immunoblotting revealed significant reductions in the abundance of proximal tubule Na(+) transporters: NHE-3 (3 +/- 1%), NaPi-2 (53 +/- 12%), and Na-K-ATPase (74 +/- 5%). In contrast, the abundance of the distal tubule Na-Cl cotransporter (TSC) was markedly increased (240 +/- 29%), whereas BSC-1 in the thick ascending limb was not altered. In conclusion, 1) increased urine output and reduced urinary concentration in nifedipine-treated-rats may, in part, be due to downregulation of AQP2 and p-AQP2 levels; 2) CaR might be involved in the regulation of water reabsorption in the inner medulla collecting duct; 3) reduced expression of proximal tubule Na(+) transporters (NHE-3, NaPi-2, and Na, K-ATPase) may be involved in the increased urinary sodium excretion; and 4) increase in TSC expression may occur as a compensatory mechanism.
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PMID:Altered expression of renal aquaporins and Na(+) transporters in rats treated with L-type calcium blocker. 1135 65

CLC-K2, a kidney-specific member of the CLC chloride channel family, is thought to play an important role in the transepithelial Cl(-) transport in the kidney. This consensus was first reached shortly after it was demonstrated that the mutations of the human CLCNKB gene resulted in Bartter's syndrome type III. To clarify the pathogenesis, the exact intrarenal and cellular localization of CLC-K2 by immunohistochemistry of the Clcnk1-/- mouse kidney were investigated by use of an anti-CLC-K antibody that recognized both CLC-K1 and CLC-K2. CLC-K2 is expressed in the thick ascending limb of Henle's loop and distal tubules, where it is localized to the basolateral membranes. The localization of CLC-K2 to these nephron segments strongly implies that CLC-K2 confers the basolateral chloride conductance in the thick ascending limb of Henle's loop and distal tubules, where Cl(-) is taken up by the bumetanide-sensitive Na-K-2Cl cotransporter or the thiazide-sensitive Na-Cl cotransporter at the apical membranes. CLC-K2 expression was also shown to extend into the connecting tubule in the basolateral membrane. CLC-K2 was found in basolateral membranes of the type A intercalated cells residing along the collecting duct. This localization strongly suggests that CLC-K2 confers the basolateral conductance in the type A intercalated cells where Cl(-) is taken up by the anion exchanger in exchange for HCO(3)(-) at the basolateral membranes. These aspects of CLC-K2 localization suggest that CLC-K2 is important in Cl(-) transport in the distal nephron segments.
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PMID:Intrarenal and cellular localization of CLC-K2 protein in the mouse kidney. 1213 29


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