Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Clin Invest
2007 Nov 01;11711:3403-11. doi: 10.1172/JCI32033.
Show Gene links
Show Anatomy links
The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex.
Yang CL
,
Zhu X
,
Ellison DH
.
???displayArticle.abstract???
The pathogenesis of essential hypertension remains unknown, but thiazide diuretics are frequently recommended as first-line treatment. Recently, familial hyperkalemic hypertension (FHHt) was shown to result from activation of the thiazide-sensitive Na-Cl cotransporter (NCC) by mutations in WNK4, although the mechanism for this effect remains unknown. WNK kinases are unique members of the human kinome, intimately involved in maintaining electrolyte balance across cell membranes and epithelia. Previous work showed that WNK1, WNK4, and a kidney-specific isoform of WNK1 interact to regulate NCC activity, suggesting that WNK kinases form a signaling complex. Here, we report that WNK3, another member of the WNK kinase family expressed by distal tubule cells, interacts with WNK4 and WNK1 to regulate NCC in both human kidney cells and Xenopus oocytes, further supporting the WNK signaling complex hypothesis. We demonstrate that physiological regulation of NCC in oocytes results from antagonism between WNK3 and WNK4 and that FHHt-causing WNK4 mutations exert a dominant-negative effect on wild-type (WT) WNK4 to mimic a state of WNK3 excess. The results provide a mechanistic explanation for the divergent effects of WT and FHHt-mutant WNK4 on NCC activity, and for the dominant nature of FHHt in humans and genetically modified mice.
Bindels,
A molecular switch controlling renal sodium and potassium excretion.
2003, Pubmed,
Xenbase
Bindels,
A molecular switch controlling renal sodium and potassium excretion.
2003,
Pubmed
,
Xenbase
Cai,
WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells.
2006,
Pubmed
,
Xenbase
Chobanian,
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.
2003,
Pubmed
Cope,
WNK1 affects surface expression of the ROMK potassium channel independent of WNK4.
2006,
Pubmed
,
Xenbase
Gamba,
Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters.
2005,
Pubmed
Gamba,
Role of WNK kinases in regulating tubular salt and potassium transport and in the development of hypertension.
2005,
Pubmed
Golbang,
A new kindred with pseudohypoaldosteronism type II and a novel mutation (564D>H) in the acidic motif of the WNK4 gene.
2005,
Pubmed
,
Xenbase
Hernando,
Kidney kinase network regulates renal ion cotransport.
2007,
Pubmed
Holden,
Cloning, genomic organization, alternative splicing and expression analysis of the human gene WNK3 (PRKWNK3).
2004,
Pubmed
Jiang,
Identification of WNK1 as a substrate of Akt/protein kinase B and a negative regulator of insulin-stimulated mitogenesis in 3T3-L1 cells.
2005,
Pubmed
Kahle,
WNK kinases: molecular regulators of integrated epithelial ion transport.
2004,
Pubmed
Kahle,
WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion.
2003,
Pubmed
,
Xenbase
Kahle,
WNK protein kinases modulate cellular Cl- flux by altering the phosphorylation state of the Na-K-Cl and K-Cl cotransporters.
2006,
Pubmed
Lalioti,
Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule.
2006,
Pubmed
Lazrak,
Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms.
2006,
Pubmed
Lenertz,
Properties of WNK1 and implications for other family members.
2005,
Pubmed
Leng,
WNK3, a kinase related to genes mutated in hereditary hypertension with hyperkalaemia, regulates the K+ channel ROMK1 (Kir1.1).
2006,
Pubmed
,
Xenbase
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
Meneton,
Sodium and potassium handling by the aldosterone-sensitive distal nephron: the pivotal role of the distal and connecting tubule.
2004,
Pubmed
O'Reilly,
Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo.
2006,
Pubmed
,
Xenbase
Pacheco-Alvarez,
The Na+:Cl- cotransporter is activated and phosphorylated at the amino-terminal domain upon intracellular chloride depletion.
2006,
Pubmed
,
Xenbase
Reilly,
Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy.
2000,
Pubmed
Rinehart,
WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis.
2005,
Pubmed
,
Xenbase
Rossier,
Negative regulators of sodium transport in the kidney: key factors in understanding salt-sensitive hypertension?
2003,
Pubmed
Subramanya,
Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform.
2006,
Pubmed
,
Xenbase
Veríssimo,
WNK kinases, a novel protein kinase subfamily in multi-cellular organisms.
2001,
Pubmed
Veríssimo,
Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway.
2006,
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
Wade,
WNK1 kinase isoform switch regulates renal potassium excretion.
2006,
Pubmed
,
Xenbase
Wang,
Comparison of WNK4 and WNK1 kinase and inhibiting activities.
2004,
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
Xie,
Role of with-no-lysine [K] kinases in the pathogenesis of Gordon's syndrome.
2006,
Pubmed
Xu,
WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II.
2000,
Pubmed
Xu,
Regulation of WNK1 by an autoinhibitory domain and autophosphorylation.
2002,
Pubmed
Yang,
Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport.
2005,
Pubmed
Yang,
Regulation of apical localization of the thiazide-sensitive NaCl cotransporter by WNK4 in polarized epithelial cells.
2005,
Pubmed
,
Xenbase
Yang,
Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model.
2007,
Pubmed
Yang,
WNK kinases regulate thiazide-sensitive Na-Cl cotransport.
2003,
Pubmed
,
Xenbase
Zambrowicz,
Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.
2003,
Pubmed
