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Hypertension
2014 Nov 01;645:1047-53. doi: 10.1161/HYPERTENSIONAHA.114.04036.
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WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4.
Chávez-Canales M
,
Zhang C
,
Soukaseum C
,
Moreno E
,
Pacheco-Alvarez D
,
Vidal-Petiot E
,
Castañeda-Bueno M
,
Vázquez N
,
Rojas-Vega L
,
Meermeier NP
,
Rogers S
,
Jeunemaitre X
,
Yang CL
,
Ellison DH
,
Gamba G
,
Hadchouel J
.
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The with-no-lysine (K) kinases, WNK1 and WNK4, are key regulators of blood pressure. Their mutations lead to familial hyperkalemic hypertension (FHHt), associated with an activation of the Na-Cl cotransporter (NCC). Although it is clear that WNK4 mutants activate NCC via Ste20 proline-alanine-rich kinase, the mechanisms responsible for WNK1-related FHHt and alterations in NCC activity are not as clear. We tested whether WNK1 modulates NCC through WNK4, as predicted by some models, by crossing our recently developed WNK1-FHHt mice (WNK1(+/FHHt)) with WNK4(-/-) mice. Surprisingly, the activated NCC, hypertension, and hyperkalemia of WNK1(+/FHHt) mice remain in the absence of WNK4. We demonstrate that WNK1 powerfully stimulates NCC in a WNK4-independent and Ste20 proline-alanine-rich kinase-dependent manner. Moreover, WNK4 decreases the WNK1 and WNK3-mediated activation of NCC. Finally, the formation of oligomers of WNK kinases through their C-terminal coiled-coil domain is essential for their activity toward NCC. In conclusion, WNK kinases form a network in which WNK4 associates with WNK1 and WNK3 to regulate NCC.
Cai,
WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells.
2006, Pubmed,
Xenbase
Cai,
WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells.
2006,
Pubmed
,
Xenbase
Castañeda-Bueno,
Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process.
2012,
Pubmed
,
Xenbase
Golbang,
Regulation of the expression of the Na/Cl cotransporter by WNK4 and WNK1: evidence that accelerated dynamin-dependent endocytosis is not involved.
2006,
Pubmed
,
Xenbase
Ko,
A new model of the distal convoluted tubule.
2012,
Pubmed
Lalioti,
Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule.
2006,
Pubmed
Lenertz,
Properties of WNK1 and implications for other family members.
2005,
Pubmed
Mederle,
Loss of WNK3 is compensated for by the WNK1/SPAK axis in the kidney of the mouse.
2013,
Pubmed
Moriguchi,
WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1.
2005,
Pubmed
Na,
Disease-causing mutations in the acidic motif of WNK4 impair the sensitivity of WNK4 kinase to calcium ions.
2012,
Pubmed
Narayan,
Global noncommunicable diseases--where worlds meet.
2010,
Pubmed
Oi,
A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo.
2012,
Pubmed
,
Xenbase
Pacheco-Alvarez,
WNK3-SPAK interaction is required for the modulation of NCC and other members of the SLC12 family.
2012,
Pubmed
,
Xenbase
Richardson,
Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1.
2008,
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
San-Cristobal,
WNK3 and WNK4 amino-terminal domain defines their effect on the renal Na+-Cl- cotransporter.
2008,
Pubmed
,
Xenbase
San-Cristobal,
Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway.
2009,
Pubmed
,
Xenbase
Takahashi,
WNK4 is the major WNK positively regulating NCC in the mouse kidney.
2014,
Pubmed
Thastrup,
SPAK/OSR1 regulate NKCC1 and WNK activity: analysis of WNK isoform interactions and activation by T-loop trans-autophosphorylation.
2012,
Pubmed
Uchida,
Regulation of with-no-lysine kinase signaling by Kelch-like proteins.
2014,
Pubmed
Uchida,
Regulation of blood pressure and renal electrolyte balance by Cullin-RING ligases.
2014,
Pubmed
Vidal-Petiot,
WNK1-related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron.
2013,
Pubmed
Vidal-Petiot,
A new methodology for quantification of alternatively spliced exons reveals a highly tissue-specific expression pattern of WNK1 isoforms.
2012,
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
Wakabayashi,
Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension.
2013,
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
Xu,
WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II.
2000,
Pubmed
Yang,
The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex.
2007,
Pubmed
,
Xenbase
Yang,
Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport.
2005,
Pubmed
Yang,
WNK kinases regulate thiazide-sensitive Na-Cl cotransport.
2003,
Pubmed
,
Xenbase
