title: WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4.
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.
authors.affiliation: 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.).
authors.forename: María
authors.initials: M
authors.lastname: Chávez-Canales
authors.affiliation: 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.).
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: 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.).
authors.forename: Christelle
authors.initials: C
authors.lastname: Soukaseum
authors.affiliation: 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.).
authors.forename: Erika
authors.initials: E
authors.lastname: Moreno
authors.affiliation: 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.).
authors.forename: Diana
authors.initials: D
authors.lastname: Pacheco-Alvarez
authors.affiliation: 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.).
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Vidal-Petiot
authors.affiliation: 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.).
authors.forename: María
authors.initials: M
authors.lastname: Castañeda-Bueno
authors.affiliation: 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.).
authors.forename: Norma
authors.initials: N
authors.lastname: Vázquez
authors.affiliation: 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.).
authors.forename: Lorena
authors.initials: L
authors.lastname: Rojas-Vega
authors.affiliation: 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.).
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Meermeier
authors.affiliation: 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.).
authors.forename: Shaunessy
authors.initials: S
authors.lastname: Rogers
authors.affiliation: 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.).
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.affiliation: 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.).
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Yang
authors.affiliation: 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.).
authors.forename: David H
authors.initials: DH
authors.lastname: Ellison
authors.affiliation: 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.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gamba
authors.affiliation: 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.
authors.forename: Juliette
authors.initials: J
authors.lastname: Hadchouel
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D015778:Minor Histocompatibility Antigens; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011546:Pseudohypoaldosteronism / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*; D049992:Sodium Chloride Symporters / Q000502:physiology*; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D015778:Minor Histocompatibility Antigens; D049992:Sodium Chloride Symporters; C499024:Prkwnk4 protein, mouse; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498744:Wnk1 protein, mouse
keywords: Xenopus laevis; familial hypertensive hyperkalemia; hypertension, renal; kidney tubules, distal; mice, knockout; pseudohypoaldosteronism, type II; water-electrolyte balance
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