Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Oxytocin (OT) binds to the vasopressin V2 receptor (V2R) because of its structural similarity to arginine vasopressin (AVP). Though the affinity of OT for V2R is low, it is known that OT causes antidiuresis. To clarify the effect of OT as an agonist of V2R, we investigated the influence of acute elevation of plasma OT levels on the rat mRNA expression of V2R and aquaporin-2 (AQP2), the water channel regulated by V2R. The plasma OT level increased from 11.1+/-1.6 pg/ml to 331.0+/-67.9 pg/ml by 1 h after subcutaneousinjection of 20 microg OT. V2R mRNA expression decreased to 68.3+/-4.1% of the control at 3 h, and AQP2 mRNA expression increased to 239.3+/-26.8% of the control at 6 h. The plasma AVP level did not change significantly during the experiment. The influence of a subcutaneous injection of 20 microg OT on V2R and AQP2 mRNA expression is comparable to that of 10 microg AVP that we documented in the previous study. In conclusion, OT can downregulate V2R mRNA expression and upregulate AQP2 mRNA expression in the collecting duct as an agonist of the V2R like AVP.
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PMID:Administration of oxytocin affects vasopressin V2 receptor and aquaporin-2 gene expression in the rat. 1032 24

Nephrogenic diabetes insipidus (NDI) is associated with germline mutations in two genes: vasopressin receptor type 2 (V2(R)) in X-linked NDI, and the water channel aquaporin-2, in autosomal-recessive disease. Genetic heterogeneity is further emphasized by reports of phenotypically abnormal individuals with normal structural genes. We analyzed both genes in five Brazilian families and the aquaporin-2 gene in two Swedish families with clinical and laboratory diagnosis of NDI, by a combination of denaturing gradient gel electrophoresis (DGGE) and direct DNA sequencing. A novel polymorphism in the aquaporin-2 gene (S167S), but no disease-associated mutations in any tested individual from all seven families, was detected. In two Brazilian families, frameshift mutations were detected in the V2(R) gene: one leading to a premature stop after codon 36 and the other to a longer peptide (462 aa instead of the 373 aa wild-type protein). In two other Brazilian families, probable disease-associated missense mutations were detected: an alanine to proline at codon 163 (A163P) and an asparagine to aspartic acid at codon 85 (D85N). In one Brazilian family, both genes were structurally normal and the aquaporin-2 gene was also normal in the two Swedish kindreds. This report further extends the mutational spectrum of NDI and suggests that there are other mutational or epigenetic events inactivating the two known genes or even novel genes that underlie NDI.
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PMID:Molecular analyses of the vasopressin type 2 receptor and aquaporin-2 genes in Brazilian kindreds with nephrogenic diabetes insipidus. 1047 31

The central and peripheral mechanisms regulate body water balance near an ideal set point. Osmosensitive neurons in the organum vasculosum lamina terminalis (OVLT) in the anterior hypothalamus play a key role in regulating vasopressin release and drinking behaviour. Patients with OVLT lesions are known to have osmostat fluctuations. Although the brain water channel is suggested to participate in osmoreception, the precise molecular mechanisms of osmoreception and thirst appreciation remain to be clarified. Vasopressin gene mutation is responsible for hereditary central diabetes insipidus. Mutant vasopressin precursors have been reported to impair the secretion of wild-type proteins or cause cellular toxicity. Despite the intact production and secretion of vasopressin, the kidney is unable to concentrate urine in nephrogenic diabetes insipidus (NDI). Most congenital NDI patients have mutations in the G protein-coupled vasopressin V2 receptor gene. V2 receptor mutants are shown not to reach the plasma membrane, not to bind AVP, and not to trigger an intracellular cyclic adenosine-monophosphate signal. Congenital NDI with an autosomal recessive inheritance has mutations of Aquaporin-2 gene, a vasopressin-sensitive water channel in the renal inner medullary collecting duct (IMCD). Aquaporin-2 mutant proteins cannot be expressed at the luminal membrane. The corticopapillary osmotic gradient is necessary for renal sensitivity to vasopressin. The vasopressin-regulated urea transporter in IMCD and the chloride channel (CLC-K1) in the ascending loop of the Henle contribute to the formation of the osmotic gradient. NDI has been shown in mice lacking the CLC-K1. The pathophysiological significance of urea transporter and CLC-K1 has yet to be demonstrated in patients with NDI.
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PMID:[Water metabolism and its disturbances]. 1063 21

Aquaporin-2 (AQP2) water channel mutations cause autosomal recessive and dominant nephrogenic diabetes insipidus. Expressed in oocytes, a mutant in dominant (AQP2-E258K), but not in recessive (AQP2-R187C), NDI conferred a specific dominant-negative effect (DNE) on wild-type (WT) AQP2 water permeability (P(f)) but only at low expression levels. Here, we determined the cell biological basis for this requirement. Injection of different amounts of WT-AQP2 cRNAs revealed that a correlation between AQP2 protein levels and P(f) is only obtained with low expression levels. In coexpression studies of WT- and mutant AQP2 proteins, higher expression levels of AQP2-R187C also exerted a DNE on the P(f) of WT-AQP2. Immunoblot and immunoprecipitation analysis revealed that this DNE was caused by competitive inhibition of WT-AQP2 expression and escape of AQP2-R187C from the endoplasmic reticulum, resulting in oligomerization with WT-AQP2. Because many disease-related mutants of multimeric renal membrane transporters and channels are likely to be identified, our data provide important information for studying the effects of such mutants on the activity of WT transporters and channels in oocytes.
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PMID:Importance of aquaporin-2 expression levels in genotype -phenotype studies in nephrogenic diabetes insipidus. 1099 28

X-Linked nephrogenic diabetes insipidus (NDI), which accounts for 90% of inherited cases of NDI, is caused by mutations in the AVPR2 gene that encodes the arginine vasopressin (AVP) receptor type 2 (V2R). The V2R mediates the antidiuretic action of AVP in principal cells of the collecting duct. To date, only three AVPR2 mutations (P322S, D85N, and G201D) have been associated with a mild NDI phenotype, and intrafamilial phenotype variability has not been reported in affected males. We describe a novel Belgian family with X-linked NDI caused by substitution of a histidine for an arginine at position 137 (R137H) of AVPR2. This mutation has been identified in two brothers and their mother. The R137H mutation results in a failure of V2R to stimulate adenylate cyclase and has been associated consistently with severe NDI and the inability to increase urinary osmolality to greater than plasma osmolality during water deprivation and/or infusion of 1-desamino-8-d-arginine vasopressin. Detailed examination of the two affected brothers showed the typical NDI phenotype in the 45-year-old proband, whereas a milder clinical phenotype associated with significant urinary concentrating ability during water deprivation was documented in the 33-year-old brother. Thus, in this family, the R137H mutation is associated with either a mild or severe NDI phenotype. Mechanisms that might account for these findings include genetic and/or environmental modifiers.
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PMID:Intrafamilial phenotype variability in nephrogenic diabetes insipidus. 1192 Mar 39

Alterations in water metabolism are present in conditions such as diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, cardiac failure, cirrhosis, and pregnancy. Recent advances in molecular biology have enhanced our understanding of disordered water metabolism in these conditions. This review examines the roles of central vasopressin synthesis and release and collecting duct vasopressin V2 receptor and aquaporin-2 water channel regulation in water-losing and water-retaining states.
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PMID:Water-losing and water-retaining states: role of water channels and vasopressin receptor antagonists. 1197 94

The present study was intended to determine whether the long-term V2 receptor-mediated effects of vasopressin on sodium reabsorption in the renal collecting duct is an aggravating factor in salt-sensitive hypertension. Deoxycorticosterone acetate (DOCA)-salt hypertension was induced in uninephrectomized rats that had been chronically pretreated with a V2 agonist (dDAVP; 1-deamino-8D-arginine vasopressin; 0.6 microg/kg.d) or a V2 antagonist (SR121463, 3 mg/kg.d) or were untreated. Plasma osmolality and natremia were not significantly different in the groups. Blood pressure was significantly increased by dDAVP pretreatment (+11 mm Hg; P = 0.006), and this effect was exacerbated after DOCA-salt-induced hypertension (+17 mm Hg; P = 0.042). The dDAVP-treated rats had a lower hematocrit (40 +/- 2% vs. 47 +/- 1% and 45 +/- 2%) and markedly higher albuminuria (91 +/- 9 vs. 17 +/- 8 and 15 +/- 8 mg/d), mortality rate (50% vs. 0% and 0%), and cardiac and renal hypertrophy than the control and SR121463 groups. Histological renal lesions were worsened by V2 agonism and prevented by V2 antagonism. Renal mRNA expression of beta- and gamma-subunits of the epithelial sodium channel was significantly increased by dDAVP treatment (P < 0.05). These findings provide evidence that chronic stimulation of vasopressin V2 receptor raises basal blood pressure in rats and exacerbates the development of DOCA-salt hypertension, organ damage, and mortality. These effects could be due at least in part to the sustained stimulation of sodium reabsorption by epithelial sodium channel in the distal part of the nephron, which promotes sodium retention.
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PMID:Chronic V2 vasopressin receptor stimulation increases basal blood pressure and exacerbates deoxycorticosterone acetate-salt hypertension. 1207 11

The aquaporin-2 (AQP2) water channel is mainly located in the apical plasma membrane of collecting duct epithelial cells, but there has been some evidence of a moderate amount of basolateral localization of AQP2 at least in the inner medullary collecting duct (IMCD). Previous in vitro microperfusion studies showed that oxytocin has an antidiuretic action, most likely mediated by the vasopressin V2 receptor (V2R) in rat IMCD. By using immunohistochemistry in kidneys from male Sprague-Dawley rats, we observed acute effects of oxytocin on AQP2 localization which were prevented by a V2R antagonist. After intraperitoneal administration of oxytocin (10 U), immunohistochemistry of IMCD revealed that AQP2 was shifted from diffuse cytoplasmic localization in controls to the apical and basolateral membrane domains in oxytocin-treated rats. This pattern of AQP2 redistribution was noted in connecting tubule, cortical collecting duct and outer medullary collecting duct as well as in IMCD, although the tendency to basolateral localization was somewhat less. The pretreatment using a V2R antagonist blocked redistribution of AQP2 in response to oxytocin. We conclude that oxytocin induces a V2R-mediated redistribution of AQP2-containing cytoplasmic vesicles to both apical and basolateral plasma membrane domains in rat kidney. Oxytocin may be one of the factors that accounts for vasopressin-independent AQP2 targeting in the kidney.
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PMID:Oxytocin induces apical and basolateral redistribution of aquaporin-2 in rat kidney. 1241 48

The polycystic kidney diseases (PKDs) are a group of genetic disorders causing significant renal failure and death in children and adults. There are no effective treatments. Two childhood forms, autosomal recessive PKD (ARPKD) and nephronophthisis (NPH), are characterized by collecting-duct cysts. We used animal models orthologous to the human disorders to test whether a vasopressin V2 receptor (VPV2R) antagonist, OPC31260, would be effective against early or established disease. Adenosine-3',5'-cyclic monophosphate (cAMP) has a major role in cystogenesis, and the VPV2R is the major cAMP agonist in the collecting duct. OPC31260 administration lowered renal cAMP, inhibited disease development and either halted progression or caused regression of established disease. These results indicate that OPC31260 may be an effective treatment for these disorders and that clinical trials should be considered.
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PMID:Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. 1450 83

Inhibition of clathrin-mediated endocytosis by expression of a GTPase-deficient dynamin mutant (dynamin-2/K44A) for 16 h results in an accumulation of plasma membrane aquaporin-2 (AQP2) in epithelial cells stably transfected with wild-type AQP2. We now show a similar effect of K44A dynamin in LLC-PK1 cells transfected with an S256 phosphorylation-deficient AQP2 mutant, AQP2(S256A), and in AQP2-transfected inner medullary collecting duct (IMCD) cells. More acute blockade of endocytosis in these cells with the cholesterol-depleting agent methyl-beta-cyclodextrin (mbetaCD; 10 mM) resulted in a rapid and extensive cell-surface accumulation of both wild-type AQP2 and AQP2 (S256A) within 15 min after treatment. This effect was similar to that induced by treatment of the cells with vasopressin. Blockade of endocytosis by mbetaCD was confirmed using quantitative analysis of FITC-dextran uptake and AQP2 membrane insertion was verified by cell-surface biotinylation. These data indicate that AQP2 recycles constitutively and rapidly between intracellular stores and the cell surface in LLC-PK1 and IMCD cells. The constitutive trafficking process is not dependent on phosphorylation of the serine-256 residue of AQP2, which is, however, an essential step for regulated vasopressin/cAMP-mediated translocation of AQP2. Our data show that rapid and extensive plasma membrane accumulation of AQP2 can occur in a vasopressin receptor (V2R)- and phosphorylation-independent manner, pointing to a potential means of bypassing the mutated V2R in X-linked nephrogenic diabetes insipidus to achieve cell surface expression of AQP2.
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PMID:Inhibition of endocytosis causes phosphorylation (S256)-independent plasma membrane accumulation of AQP2. 1451 93


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