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

María Chávez-Canales; Chong Zhang; Christelle Soukaseum; Erika Moreno; Diana Pacheco-Alvarez; Emmanuelle Vidal-Petiot; María Castañeda-Bueno; Norma Vázquez; Lorena Rojas-Vega; Nicholas P Meermeier; Shaunessy Rogers; Xavier Jeunemaitre; Chao-Ling Yang; David H Ellison; Gerardo Gamba; Juliette Hadchouel

doi:10.1161/HYPERTENSIONAHA.114.04036

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. Epub 2014 Aug 11.

Authors

María Chávez-Canales¹, Chong Zhang¹, Christelle Soukaseum¹, Erika Moreno¹, Diana Pacheco-Alvarez¹, Emmanuelle Vidal-Petiot¹, María Castañeda-Bueno¹, Norma Vázquez¹, Lorena Rojas-Vega¹, Nicholas P Meermeier¹, Shaunessy Rogers¹, Xavier Jeunemaitre¹, Chao-Ling Yang¹, David H Ellison¹, Gerardo Gamba², Juliette Hadchouel²

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.). [email protected] [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Pressure / physiology
Disease Models, Animal
Female
Humans
In Vitro Techniques
Kidney / physiopathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Mutant Strains
Minor Histocompatibility Antigens
Phenotype
Protein Serine-Threonine Kinases / deficiency
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / physiology*
Pseudohypoaldosteronism / physiopathology
Signal Transduction / physiology*
Sodium Chloride Symporters / physiology*
WNK Lysine-Deficient Protein Kinase 1

Substances

Minor Histocompatibility Antigens
Sodium Chloride Symporters
Prkwnk4 protein, mouse
Stk39 protein, mouse
Protein Serine-Threonine Kinases
WNK Lysine-Deficient Protein Kinase 1
Wnk1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding