Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Foxa1 is a member of the winged helix family of transcription factors and is expressed in the collecting ducts of the kidney. We investigated its potential contribution to renal physiology in Foxa1-deficient mice on a defined genetic background. Foxa1(-/-) mice are dehydrated and exhibit electrolyte imbalance as evidenced by elevated hematocrit and plasma urea levels, hypernatremia, and hyperkalemia. This phenotype is the consequence of decreased urine osmolality secondary to renal vasopressin resistance. Mutations of the human genes encoding the vasopressin 2 receptor and aquaporin 2 cause nephrogenic diabetes insipidus; however, expression of these genes is maintained or increased, respectively, in Foxa1(-/-) mice. Likewise, expression of the genes encoding the Na-K-2Cl cotransporter (NKCC2), the potassium channel ROMK, the chloride channel CLCNKB, barttin (BSND), and the calcium-sensing receptor (CASR), each of which is important in sodium reabsorption in the loop of Henle, is maintained or even increased in Foxa1-deficient mice. Thus, we have shown that Foxa1(-/-) mice represent a new model of nephrogenic diabetes insipidus with unique molecular etiology, and we have identified the first transcription factor whose mutation leads to a defect in renal water homeostasis in vivo.
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PMID:Mild nephrogenic diabetes insipidus caused by Foxa1 deficiency. 1525 40

Vasopressin-stimulated insertion of the aquaporin 2 (AQP2) water channel into the plasma membrane of kidney collecting duct principal cells is a key event in the urinary concentrating mechanism. The paradigm for vasopressin-receptor signaling involves cAMP-mediated protein kinase A activation, which results in the functionally critical phosphorylation of AQP2 on amino acid serine 256. We previously showed that a parallel cGMP-mediated signaling pathway also leads to AQP2 membrane insertion in AQP2-transfected LLC-PK1 (LLC-AQP2) cells and in outer medullary collecting duct principal cells in situ (Bouley R, Breton S, Sun T, McLaughlin M, Nsumu NN, Lin HY, Ausiello DA, and Brown D. J Clin Invest 106: 1115-1126, 2000). In the present report, we show by immunofluorescence microscopy, and Western blotting of plasma membrane fractions, that 45-min exposure of LLC-AQP2 cells to the cGMP phosphodiesterase type 5 (PDE5) inhibitors sildenafil citrate (Viagra) or 4-{[3',4'-methylene-dioxybenzyl]amino}-6-methoxyquinazoline elevates intracellular cGMP levels and results in the plasma membrane accumulation of AQP2; i.e., they mimic the vasopressin effect. Importantly, our data also show that acute exposure to PDE5 inhibitors for 60 min induces apical accumulation of AQP2 in kidney medullary collecting duct principal cells both in tissue slices incubated in vitro as well as in vivo after intravenous injection of Viagra into rats. These data suggest that AQP2 membrane insertion can be induced independently of vasopressin-receptor activation by activating a parallel cGMP-mediated signal transduction pathway with cGMP PDE inhibitors. These results provide proof-of-principle that pharmacological activation of vasopressin-independent, cGMP signaling pathways could aid in the treatment of those forms of nephrogenic diabetes insipidus that are due to vasopressin-2 receptor dysfunction.
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PMID:Stimulation of AQP2 membrane insertion in renal epithelial cells in vitro and in vivo by the cGMP phosphodiesterase inhibitor sildenafil citrate (Viagra). 1564 88

Vasopressin is a nonapeptide synthesised in the hypothalamus and released upon stimulations such as hyperosmolality, hypotension and hypovolaemia. In acute shock states serum vasopressin levels increase rapidly and decrease in prolonged septic shock. The administration of vasopressin in healthy subjects has little effect, whereas in vasodilatory shock it increases the mean arterial pressure through V1 receptors and decreases the cardiac output. Vasopressin stimulates the V2 receptors in the kidney leading to reabsorption of water through aquaporin 2. However, in vasodilatory shock the antidiuretic effects are overcome by the effect vasopressin has on the kidneys: improvement of renal blood flow leading to water excretion. Twenty-four studies on the use of vasopressin in patients with vasodilatory shock are reviewed. They show that vasopressin potentiates norepinephrine effects, increases blood pressure significantly in patients with vasodilatory shock and may improve renal function. Side effects ranging from ischaemic skin lesions to possible intestinal ischaemia should not be underestimated. Above a dose of 0.04 U/min it may lead to cardiac arrest. Effects on mortality cannot be interpreted from these studies. Broad clinical use should await controlled trials to clarify its effects on clinical outcomes such as organ failure and mortality.
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PMID:Vasopressin: physiology and clinical use in patients with vasodilatory shock: a review. 1571 46

In addition to its effect on water permeability, vasopressin, through its V2 receptors (AVPR2), stimulates Na reabsorption in the collecting duct by increasing the activity of the amiloride-sensitive sodium channel ENaC. This study evaluated whether dDAVP (a potent AVPR2 agonist) reduces sodium excretion in healthy humans (n = 6) and in patients with central (C; n = 2) or nephrogenic (N) diabetes insipidus (DI) as a result of mutations of either the aquaporin 2 gene (AQP2; n = 3) or AVPR2 (n = 10). dDAVP was infused intravenously (0.3 microg/kg body wt in 20 min), and urine was collected for 60 min before (basal) and 150 min after the infusion. dDAVP markedly reduced both urine flow rate and sodium excretion in healthy individuals. A reduction in sodium excretion was also observed in CDI and NDI-AQP2 patients but not in NDI-AVPR2 patients. The magnitude of the fall in sodium excretion correlated with the rise in urine osmolality and the fall in urine output but not with the simultaneously observed fall in mean BP. These results suggest that the dDAVP-induced antinatriuresis is due to a direct V2 receptor-dependent stimulation of sodium reabsorption in the collecting duct and is not secondary to a hemodynamic effect. In conclusion, this study reveals a potent V2-dependent antinatriuretic effect of vasopressin in humans. The possibility that an inappropriate stimulation of ENaC by vasopressin might lead to significant sodium retention in chronic situations remains to be determined.
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PMID:Vasopressin-V2 receptor stimulation reduces sodium excretion in healthy humans. 1588 62

The identification, characterization, and mutational analysis of three different genes-the arginine vasopressin gene (AVP), the arginine vasopressin receptor 2 gene (AVPR2), and the vasopressin-sensitive water channel gene (aquaporin 2 [AQP2])-provide the basis for understanding of three different hereditary forms of "pure" diabetes insipidus: Neurohypophyseal diabetes insipidus, X-linked nephrogenic diabetes insipidus (NDI), and non-X-linked NDI, respectively. It is clinically useful to distinguish two types of hereditary NDI: A "pure" type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients who have congenital NDI and bear mutations in the AVPR2 or AQP2 genes have a "pure" NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride, and calcium. Patients who bear inactivating mutations in genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA and CLCNKB in combination, or BSND) that encode the membrane proteins of the thick ascending limb of the loop of Henle have a complex polyuro-polydipsic syndrome with loss of water, sodium, chloride, calcium, magnesium, and potassium. These advances provide diagnostic and clinical tools for physicians who care for these patients.
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PMID:Molecular biology of hereditary diabetes insipidus. 1609 48

Bradykinin (BK) is one of the most important peptides regulating vascular tone, water, and ionic balance in the body, playing a key role in controlling BP. It is interesting that patients with essential hypertension excrete less BK than normotensive individuals. For elucidating the mechanism by which BK regulates renal water transport that contributes to its antihypertensive effect, aquaporin 2 (AQP2)-transfected collecting duct CD8 cells, expressing the BK type II receptor (BK2R), were used as an experimental model. In CD8 cells, BK pretreatment impaired forskolin-induced AQP2 translocation to the apical plasma membrane. For clarifying the signal transduction cascade associated with this effect, whether BK induced an increase in cytosolic calcium, via the G protein Gq, known to be coupled to BK2R, first was investigated. Spectrofluorometry using fura-2-AM revealed that 100 nM BK elicited a significant increase in Ca(i), which was abolished by the receptor antagonist HOE-140. BK acts through BK2R coupled to both Gq and Galpha13, a known upstream effector of Rho protein. In CD8 cells, BK causes an increase in Rho activity, likely as a result of Galpha13 activation. This results in stabilization of the cortical F-actin network, thus impairing AQP2 trafficking. These effects counteract physiologic vasopressin stimulation, which instead has an opposite effect on actin network organization through Rho inactivation.
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PMID:Bradykinin signaling counteracts cAMP-elicited aquaporin 2 translocation in renal cells. 1609 49

The mammalian renal collecting duct increases its water permeability in response to antidiuretic hormone (ADH). ADH causes cytoplasmic endosomes containing the water channel, aquaporin 2 (AQP 2), to fuse with the apical membrane so that the water permeability of the tubule increases many times above baseline. SNARE proteins are involved in the docking and fusion of vesicles with the cell membrane in neuron synapses. Whether these proteins are involved in the fusion of vesicles to the cell membrane in other tissues is not entirely clear. In the present study, we examined the role of SNARE proteins in the insertion of water channels in the collecting-duct response to ADH by using botulinum toxins A, B and C. Toxins isolated from clostridium botulinum are specific proteases that cleave different SNARE proteins and inactivate them. Tubules were perfused in vitro with botulinum toxin in the perfusate (50 nM for A and B and 15 nM for C). ADH (200 pM) was then added to the bath after baseline measurements of osmotic water permeability (P(f)) and the change in P(f) was followed for one hour. Botulinum toxins significantly inhibited the maximum P(f) by approximately 50%. Botulinum toxins A and C also decreased the rate of rise of P(f). Thus, SNARE proteins are involved in the insertion of the water channels in the collecting duct.
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PMID:Botulinum toxins inhibit the antidiuretic hormone (ADH)-stimulated increase in rabbit cortical collecting-tubule water Permeability. 1624 33

There is evidence to suggest that water homeostasis in the inner ear is regulated via the vasopressin (VP)-aquaporin 2 (AQP2) system in the same fashion as in the kidney. The VP-AQP2 system in the kidney is well known to be inhibited by lithium, resulting in polyuria due to a decrease in reabsorption of water in the collecting duct of the kidney. Therefore, lithium is also likely to inhibit the VP-AQP2 system in the inner ear, and consequently exert some influence on inner ear fluid homeostasis. In this study, we investigated the effects of lithium on AQP2 expression in the rat inner ear, and on the cochlear fluid volume in hydropic ears of guinea pigs. A quantitative PCR study revealed that lithium reduced AQP2 mRNA expression in the cochlea and endolymphatic sac. Lithium application also decreased the immunoreactivity of AQP2 in the cochlea and endolymphatic sac. In a morphological study, lithium intake significantly reduced endolymphatic hydrops dose-dependently. These results indicate that lithium acts on the VP-AQP2 system in the inner ear, consequently producing a dehydratic effect on the endolymphatic compartment.
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PMID:Effects of lithium on endolymph homeostasis and experimentally induced endolymphatic hydrops. 1637 61

We used the mouse nephrin promoter to express a constitutively active Galphaq [Galphaq(Q>L)] transgene in mice. As previously reported, the transgene was expressed in kidney, pancreas, and brain, and the kidney phenotype was characterized by albuminuria and reduced nephron mass. Additional studies revealed a second phenotype characterized by polyuria and polydipsia. The polyuric phenotype was not caused by abnormal glucose metabolism or hypercalcemia but was accompanied by reduced urinary concentrating ability. Additional studies found that 1) water restriction was associated with an appropriate increase in serum vasopressin levels in transgenic (TG) mice; 2) the urinary concentrating defect was not corrected by administration of desamino-d-arginine vasopressin (DDAVP); and 3) papillary length was similar in TG and non-TG mice. To examine the renal response to DDAVP at the molecular level, we monitored aquaporin 2 (AQP2) and vasopressin V2 receptor (V2R) mRNA levels in mouse kidney. Consistent with the known effects of vasopressin, administration of DDAVP caused a decrease in V2R mRNA levels and an increase in AQP2 mRNA levels in both TG and non-TG animals, suggesting an appropriate renal response to DDAVP in the TG mice. To determine whether the urine concentrating abnormality was the result of primary polydipsia, water intake by TG mice was restricted to the amount ingested by non-TG animals. After 5 days, urinary concentrating ability was similar in TG mice and non-TG littermate controls. These data are consistent with the notion that expression of the Galphaq(Q>L) transgene in the brain induced primary polydipsia in the TG mice.
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PMID:Galphaq-dependent signaling cascades stimulate water-seeking behavior. 1660 48

The serine/threonine phosphatase calcineurin is an important signaling molecule involved in kidney development and function. One potential target of calcineurin action is the water channel aquaporin 2 (AQP2). In this study, we examined the effect of loss of calcineurin Aalpha (CnAalpha) on AQP2 function in vivo. CnAalpha null mice were found to have defective post-natal urine-concentrating ability and an impaired urine-concentrating response to vasopressin. Expression of AQP2 is normal but, paradoxically, vasopressin-mediated phosphorylation of the channel is decreased compared with wild-type littermates and there is no accumulation of AQP2 in the apical membrane. Calcineurin protein and activity was found in innermedullary collecting duct vesicles, and loss of calcineurin expression and activity was associated with a loss of AQP2 in the vesicle fraction. As such, the lack of vasopressin-mediated phosphorylation of AQP2 might be the result of a defect in normal trafficking of AQP2 to apical-targeted vesicles. Likewise, treatment of wild-type mice with cyclosporin A to inhibit calcineurin produces a similarly impaired urine-concentrating response to vasopressin and alterations in AQP2 phosphorylation and trafficking. These experiments demonstrate that, CnAalpha is required for normal intracellular trafficking of AQP2 and loss of calcineurin protein or activity disrupts AQP2 function.
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PMID:Loss of calcineurin Aalpha results in altered trafficking of AQP2 and in nephrogenic diabetes insipidus. 1673 44


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