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Proc Natl Acad Sci U S A
2012 May 15;10920:7929-34. doi: 10.1073/pnas.1200947109.
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Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process.
Castañeda-Bueno M
,
Cervantes-Pérez LG
,
Vázquez N
,
Uribe N
,
Kantesaria S
,
Morla L
,
Bobadilla NA
,
Doucet A
,
Alessi DR
,
Gamba G
.
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Pseudohypoaldosteronism type II is a salt-sensitive form of hypertension with hyperkalemia in humans caused by mutations in the with-no-lysine kinase 4 (WNK4). Several studies have shown that WNK4 modulates the activity of the renal Na(+)Cl(-) cotransporter, NCC. Because the renal consequences of WNK4 carrying pseudoaldosteronism type II mutations resemble the response to intravascular volume depletion (promotion of salt reabsorption without K(+) secretion), a condition that is associated with high angiotensin II (AngII) levels, it has been proposed that AngII signaling might affect WNK4 modulation of the NCC. In Xenopus laevis oocytes, WNK4 is required for modulation of NCC activity by AngII. To demonstrate that WNK4 is required in the AngII-mediated regulation of NCC in vivo, we used a total WNK4-knockout mouse strain (WNK4(-/-)). WNK4 mRNA and protein expression were absent in WNK4(-/-) mice, which exhibited a mild Gitelman-like syndrome, with normal blood pressure, increased plasma renin activity, and reduced NCC expression and phosphorylation at T-58. Immunohistochemistry revealed normal morphology of the distal convoluted tubule with reduced NCC expression. Low-salt diet or infusion of AngII for 4 d induced phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and of NCC at S-383 and T-58, respectively, in WNK4(+/+) but not WNK4(-/-) mice. Thus, the absence of WNK4 in vivo precludes NCC and SPAK phosphorylation promoted by a low-salt diet or AngII infusion, suggesting that AngII action on the NCC occurs via a WNK4-SPAK-dependent signaling pathway. Additionally, stimulation of aldosterone secretion by AngII, but not by a high-K(+) diet, was impaired in WNK4(-/-) mice.
Berl,
On the mechanism of polyuria in potassium depletion. The role of polydipsia.
1977, Pubmed
Berl,
On the mechanism of polyuria in potassium depletion. The role of polydipsia.
1977,
Pubmed
Carlström,
Superoxide dismutase 1 limits renal microvascular remodeling and attenuates arteriole and blood pressure responses to angiotensin II via modulation of nitric oxide bioavailability.
2010,
Pubmed
Chiga,
Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone.
2008,
Pubmed
Crowley,
Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney.
2006,
Pubmed
Crowley,
Role of AT₁ receptor-mediated salt retention in angiotensin II-dependent hypertension.
2011,
Pubmed
Gamba,
The thiazide-sensitive Na+-Cl- cotransporter: molecular biology, functional properties, and regulation by WNKs.
2009,
Pubmed
Hackenthal,
Morphology, physiology, and molecular biology of renin secretion.
1990,
Pubmed
Hoorn,
The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension.
2011,
Pubmed
Jiang,
WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4.
2007,
Pubmed
,
Xenbase
Kahle,
Paracellular Cl- permeability is regulated by WNK4 kinase: insight into normal physiology and hypertension.
2004,
Pubmed
Kahle,
WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion.
2003,
Pubmed
,
Xenbase
Lai,
Dietary salt modulates the sodium chloride cotransporter expression likely through an aldosterone-mediated WNK4-ERK1/2 signaling pathway.
2012,
Pubmed
Lalioti,
Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule.
2006,
Pubmed
Lifton,
Molecular mechanisms of human hypertension.
2001,
Pubmed
Mayan,
Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density.
2002,
Pubmed
McCormick,
A SPAK isoform switch modulates renal salt transport and blood pressure.
2011,
Pubmed
Mu,
Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension.
2011,
Pubmed
Na,
Disease-causing mutations in the acidic motif of WNK4 impair the sensitivity of WNK4 kinase to calcium ions.
2012,
Pubmed
Pacheco-Alvarez,
The Na+:Cl- cotransporter is activated and phosphorylated at the amino-terminal domain upon intracellular chloride depletion.
2006,
Pubmed
,
Xenbase
Park,
Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature.
2011,
Pubmed
Rafiqi,
Role of the WNK-activated SPAK kinase in regulating blood pressure.
2010,
Pubmed
Richardson,
Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1.
2008,
Pubmed
Ring,
WNK4 regulates activity of the epithelial Na+ channel in vitro and in vivo.
2007,
Pubmed
,
Xenbase
San-Cristobal,
Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway.
2009,
Pubmed
,
Xenbase
San-Cristobal,
WNK kinases, renal ion transport and hypertension.
2008,
Pubmed
Sandberg,
ANG II provokes acute trafficking of distal tubule Na+-Cl(-) cotransporter to apical membrane.
2007,
Pubmed
Simon,
Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.
1996,
Pubmed
van der Lubbe,
Angiotensin II induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter independent of aldosterone.
2011,
Pubmed
Vitari,
The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases.
2005,
Pubmed
Wilson,
Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.
2003,
Pubmed
,
Xenbase
Wilson,
Human hypertension caused by mutations in WNK kinases.
2001,
Pubmed
Yamauchi,
Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins.
2004,
Pubmed
,
Xenbase
Yang,
Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model.
2007,
Pubmed
Yue,
Angiotensin II diminishes the effect of SGK1 on the WNK4-mediated inhibition of ROMK1 channels.
2011,
Pubmed
Zhao,
Enhanced distal nephron sodium reabsorption in chronic angiotensin II-infused mice.
2009,
Pubmed
