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)

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

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

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

CLC-K1, a kidney-specific chloride channel, has been demonstrated to be involved in the urine concentration mechanism. Here, we investigated the developmental expression of CLC-K1 in the rat kidney. Using immunohistochemistry, we showed that CLC-K1 was not present in the thin ascending limb of Henle's loop during the early prenatal stages but was significantly expressed during the adult stage. CLC-K1 started to appear at day 5 and its expression increased during further development. In developing rats this increase coincided with the increase in the urine-concentrating capacity as the animals matured. We also investigated the expressions of other channels and transporters, including NKCC2, AQP-1, and AQP-2. NKCC2 was strongly expressed throughout the inner medulla in neonatal rat kidneys but was entirely undetectable at the adult stage. The decline in its expression took the form of a gradual recession from the inner medulla together with reciprocal increases in the expression of CLC-K1. AQP-1 was weakly expressed in the inner medulla during early development and showed a rapid increase in expression at a later stage. The collecting duct cells significantly expressed AQP-2 even at birth and maintained its expression throughout the development. These results suggest that CLC-K1 expression is one of the major determinants of the urine-concentrating capacity of the developing rat kidney.
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PMID:Developmental expression of CLC-K1 in the postnatal rat kidney. 1147 22

Vasopressin plays a role in both salt and water balance in the kidney. Classic studies, utilizing isolated perfused tubules, have revealed that vasopressin increases sodium reabsorption in the kidney thick ascending limb and the collecting duct. Furthermore, the activity of several sodium transport proteins expressed in these segments, such as the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) and the epithelial sodium channel (ENaC), have been shown to be directly increased by vasopressin. Increased protein abundance might be one means through which sodium transporter and channel activity is enhanced. We have used immunoblotting and immunohistochemistry in order to investigate the regulation of abundance of the major sodium transporters and channels expressed along the renal tubule in response to vasopressin. Chronic (7-day) studies were performed in which vasopressin levels were elevated either endogenously by water restriction of Sprague-Dawley rats or exogenously through infusion of the vasopressin V2-receptor-selective agonist, dDAVP (1-deamino-8d-arginine-vasopressin), to Brattleboro rats. We found a significant increase in protein abundance for NKCC2 and the beta- and gamma-subunits of ENaC with either water restriction or dDAVP infusion. The alpha-subunit of Na-K-ATPase was increased by water restriction, but not by dDAVP infusion, and alpha-ENaC and the thiazide-sensitive cotransporter (NCC) were increased by dDAVP infusion but not by water restriction. Acute (60-min) in vivo exposure to dDAVP led to an increase in both beta- and gamma-ENaC abundance in kidney cortex homogenates, displaying the rapid nature of some of these changes. Overall these increases in sodium transporter and channel abundances likely contribute to both the antidiuretic and antinatriuretic actions of vasopressin.
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PMID:Regulation of the abundance of renal sodium transporters and channels by vasopressin. 1157 75

Animals with induced or natural null mutations in renal NaCl and water transporter genes provide a powerful tool to study the physiological mechanisms that enable the kidney to optimize the match between glomerular filtration rate and tubular reabsorption. Deficiencies in the Na/H exchanger NHE3 and in the water channel aquaporin 1 (AQP1) cause reductions in proximal fluid absorption which are accompanied by proportionate decrements in glomerular filtration rate (GFR). Compensation of the transport defect by a reduction in filtered load is so efficient that clinically symptomatic Na losses are not observed in either NHE3 or AQP1 deficient animals. On the other hand, severe syndromes of salt wasting are caused by loss of function of the Na,K,2Cl-cotransporter (NKCC2) in the thick ascending limb, or of the epithelial Na channel (ENaC) the collecting duct indicating that the severity of Na dysregulation is unrelated to the basal absorption of NaCl in a given nephron segment. In these states, the increased delivery of Na to downstream segments is not monitored by a sensor linked to the site of filtrate formation. In the absence of adaptations in the filtered load intrarenal compensation of a circumscribed NaCl malabsorption by adjustment of NaCl transport in other nephron segments is sometimes insufficient, particularly in the immature kidney of the newborn.
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PMID:Sodium transport deficiency and sodium balance in gene-targeted mice. 1167 27

Loop-diuretic-sensitive 86Rb+(K+) transmembrane fluxes were determined in cells of a mouse inner medullary collecting duct cell line (mIMCD-K2). The furosemide-sensitive (0.1 mM) influx was a substantial fraction of the total influx (0.39+/-0.04 or 0.42+/-0.03, n=5 in the presence or absence of ouabain, respectively). Furosemide also reduced 86Rb+(K+) efflux by a similar fraction (0.46). RT-PCR analysis revealed expression of mRNA for the Na+-K+-2Cl- cortransporter-1 (NKCC1), but not NKCC2. Loop-diuretic-sensitive 86Rb+(K+) influx was confined to the basolateral membrane, confirming its localisation there. The physiological properties of NKCC1 expressed in mIMCD-K2 cells, including the dependence upon medium Na+, K+ and Cl- and the relative sensitivity to loop diuretics as assessed by the concentration required for half-maximal inhibition (IC50) (bumetanide 3.3+/-1.4x10-7 M>piretanide 2.5+/-0.15x10-6 M>furosemide 2.3+/-1.2x10-5 M) were typical for NKCC1. Possible functions of NKCC1 were tested; furosemide did not inhibit the majority of forskolin-stimulated secretory short-circuit current (Isc) (83.5+/-5.3% of the maintained response at 5 min). Secondly, total 86Rb+(K+) influx was stimulated markedly when external osmolarity was increased to 600 mosmol/l by mannitol due to an increase via NKCC1 from 55+/-11 to 191+/-2 nmol/106 cells per 15 min, (both n=4, P<0.01). In contrast, 10-5 M forskolin did not stimulate total 86Rb+(K+) influx. Finally, the ability of both K+ and NH4+ to compete for ouabain-insensitive 86Rb+(K+) influx via NKCC1 was confirmed with similar concentrations for half-maximal influx reduction (K0.5). Apical exposure to NH4+ elicited rapid cytosolic alkalinisation in 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-loaded epithelial layers, consistent with selective permeability of the apical membrane to NH3. Conversely, NH4+ (5 mM) at the basal cell surface resulted in progressive acidification, the initial rate being reduced by 43% by furosemide. We conclude that NKCC1 participates in selective uptake of NH4+ at the basal surface, and that IMCD may function in direct NH4+ deposition to urine.
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PMID:Expression and role of sodium, potassium, chloride cotransport (NKCC1) in mouse inner medullary collecting duct (mIMCD-K2) epithelial cells. 1169 76

This study was designed to examine the effect of losartan treatment on renal tubular function in rats with mild congestive heart failure (CHF) induced by ligation of the left anterior descending artery. In rats with CHF, there was a significant decrease in daily sodium excretion, which caused sodium retention relative to control rats. Renal function studies revealed that glomerular filtration rate and proximal tubular sodium handling were normal. However, expression of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2) in the thick ascending limb of Henle's loop was increased. Moreover, vasopressin-mediated renal water reabsorption, as evaluated by the aquaretic response to selective V(2)-receptor blockade, was significantly increased. Losartan treatment normalized expression of NKCC2 and decreased expression of the vasopressin-regulated water channel aquaporin-2. This was associated with normalization of daily sodium excretion and normalization of the aquaretic response to V(2)-receptor blockade. Together, these results indicate that, in rats with CHF, losartan treatment inhibits increased sodium reabsorption through NKCC2 in the thick ascending limb of Henle's loop and water reabsorption through aquaporin-2 in the collecting ducts, which may be involved in improving renal function in losartan-treated CHF rats.
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PMID:Losartan treatment normalizes renal sodium and water handling in rats with mild congestive heart failure. 1178 45

Nitric oxide (NO) plays an important role in various physiological processes in the kidney. In vivo experiments first suggested that the natriuretic and diuretic effects caused by NO may be due to decreased NaCl and fluid absorption by the nephron. In the last 10 years, several reports have directly demonstrated a role for NO in modulating transport in different tubule segments. The effects of NO on proximal tubule transport are still controversial. Both stimulation and inhibition of net fluid and bicarbonate have been reported in this segment, whereas only inhibitory effects of NO have been found in Na/H exchanger and Na/K-ATPase activity. The effects of NO in the thick ascending limb are more homogeneous than in the proximal tubule. In this segment, NO decreases net Cl and bicarbonate absorption. A direct inhibitory effect of NO on the Na-K-2Cl cotransporter and the Na/H exchanger has been reported, while NO was found to stimulate apical K channels in this segment. In the collecting duct, NO inhibits Na absorption and vasopressin-stimulated osmotic water permeability. An inhibitory effect of NO on H-ATPase has also been reported in intercalated cells of the collecting duct. Overall, the reported effects of NO in the different nephron segments mostly agree with the natriuretic and diuretic effects observed in vivo. However, the net effect of NO on transport is still controversial in some segments, and in cases like the distal tubule, it has not been studied.
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PMID:Role of nitric oxide in the regulation of nephron transport. 1193 86

We tested whether the abundance of transport proteins involved in the urinary concentrating mechanism was altered in rats with uncontrolled diabetes mellitus (DM). Rats were injected with streptozotocin and killed 5, 10, 14, or 20 days later. Blood glucose in DM rats was 300-450 mg/dl (control: 70-130 mg/dl). Urine volume increased in DM rats from 41 +/- 7 ml/100 g body wt (BW) at 5 days to 69 +/- 3 ml/100 g BW at 20 days (control: 9 +/- 1). Urine osmolality of DM rats decreased at 5 days DM and remained low at 20 days. UT-A1 urea transporter protein in the inner medullary (IM) tip was 55% of control in 5-day DM rats but increased to 170, 220, and 280% at 10, 14, and 20 days DM, respectively, due to an increase in the 117-kDa glycoprotein form. UT-A1 in the IM base was increased to 325% of control at 5 days DM with no further increase at 20 days. Aquaporin-2 (AQP2) increased to 290% in the IM base at 5 days DM and 150% in the IM tip at 10 days; both showed no further increase at 20 days. NKCC2/BSC1 increased to 240% in outer medulla at 20 days DM, but not at 5 or 10 days. UT-B and ROMK were unchanged at any time point. The increases in UT-A1, AQP2, and NKCC2/BSC1 proteins during uncontrolled DM would tend to limit the loss of fluid and solute during uncontrolled diabetes.
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PMID:Changes in renal medullary transport proteins during uncontrolled diabetes mellitus in rats. 1269 81


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