2. Academic Validation
  3. WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4

WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4

  • Hypertension. 2014 Nov;64(5):1047-53. doi: 10.1161/HYPERTENSIONAHA.114.04036.
María Chávez-Canales 1,  Chong Zhang 1,  Christelle Soukaseum 1,  Erika Moreno 1,  Diana Pacheco-Alvarez 1,  Emmanuelle Vidal-Petiot 1,  María Castañeda-Bueno 1,  Norma Vázquez 1,  Lorena Rojas-Vega 1,  Nicholas P Meermeier 1,  Shaunessy Rogers 1,  Xavier Jeunemaitre 1,  Chao-Ling Yang 1,  David H Ellison 1,  Gerardo Gamba 2,  Juliette Hadchouel 2
Affiliations

Affiliations

  • 1 From the Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, Mexico (M.C.-C., M.C.-B., N.V., L.R.-V., G.G.); Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (M.C.-C., E.M., M.C.-B., N.V., L.R.-V., G.G.); Division of Nephrology and Hypertension, Oregon Health and Science University, Portland (C.Z., N.P.M., S.R., X.J., C.-L.Y., D.H.E.); INSERM UMR970-Paris Cardiovascular Research Center, Paris, France (C.S., E.V.-P., X.J., J.H.); Faculty of Medicine, University Paris-Descartes, Sorbonne Paris Cité, Paris, France (C.S., E.V.-P., J.H.); Escuela de Medicina, Universidad Panamericana, Mexico City, Mexico (D.P.-A.); AP-HP, Department of Genetics, Hôpital Européen Georges Pompidou, Paris, France (X.J.); and Veterans Affairs Medical Center, Portland, OR (D.H.E.).
  • 2 From the Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, Mexico (M.C.-C., M.C.-B., N.V., L.R.-V., G.G.); Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico (M.C.-C., E.M., M.C.-B., N.V., L.R.-V., G.G.); Division of Nephrology and Hypertension, Oregon Health and Science University, Portland (C.Z., N.P.M., S.R., X.J., C.-L.Y., D.H.E.); INSERM UMR970-Paris Cardiovascular Research Center, Paris, France (C.S., E.V.-P., X.J., J.H.); Faculty of Medicine, University Paris-Descartes, Sorbonne Paris Cité, Paris, France (C.S., E.V.-P., J.H.); Escuela de Medicina, Universidad Panamericana, Mexico City, Mexico (D.P.-A.); AP-HP, Department of Genetics, Hôpital Européen Georges Pompidou, Paris, France (X.J.); and Veterans Affairs Medical Center, Portland, OR (D.H.E.). juliette.hadchouel@inserm.fr gamba@biomedicas.unam.mx.
PMID: 25113964 DOI: 10.1161/HYPERTENSIONAHA.114.04036
Abstract

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.

Keywords

Xenopus laevis; familial hypertensive hyperkalemia; hypertension, renal; kidney tubules, distal; mice, knockout; pseudohypoaldosteronism, type II; water-electrolyte balance.

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