Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC


Por: Argaiz, Eduardo R., Chavez-Canales, Maria, Ostrosky-Frid, Mauricio, Rodriguez-Gama, Alejandro, Vazquez, Norma, Gonzalez-Rodriguez, Xochiquetzal, Garcia-Valdes, Jesus, Hadchouel, Juliette, Ellison, David, Gamba, Gerardo

Publicada: 1 sep 2018
Resumen:
Familial hyperkalemic hypertension (FHHt) can be mainly attributed to increased activity of the renal Na+:Cl- cotransporter (NCC), which is caused by altered expression and regulation of the with-no-lysine (K) 1 (WNK1) or WNK4 kinases. The WNK1 gene gives rise to a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the expression of which occurs primarily in the distal convoluted tubule. The role played by KS-WNK1 in the modulation of the WNK/STE20-proline-alanine rich kinase (SPAK)/NCC pathway remains elusive. In the present study, we assessed the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK pathway. Microinjection of oocytes with human KS-WNK1 cRNA induces remarkable activation and phosphorylation of SPAK and NCC. The effect of KS-WNK1 was abrogated by eliminating a WNK-WNK-interacting domain and by a specific WNK inhibitor, WNK463, indicating that the activation of SPAK/NCC by KS-WNK1 is due to interaction with another WNK kinase. Under control conditions in oocytes, the activating serine 335 of the WNK4 T loop is not phosphorylated. In contrast, this serine becomes phosphorylated when the intracellular chloride concentration([Cl-](i)) is reduced or when KS-WNK1 is coexpressed with WNK4. KS-WNK1-mediated activation of WNK4 is not due to a decrease of the [Cl-](i). Coimmunoprecipitation analysis revealed that KS-WNK1 and WNK4 interact with each other and that WNK4 becomes autophosphorylated at serine 335 when it is associated with KS-WNK1. Together, these observations suggest that WNK4 becomes active in the presence of KS-WNK1, despite a constant [Cl-](i).

Filiaciones:
Argaiz, Eduardo R.:
 Univ Nacl Autonoma Mexico, Mol Physiol Unit, Inst Invest Biomed, Mexico City, DF, Mexico

 Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Nephrol & Mineral Metab, Mexico City, DF, Mexico

 Tecnol Monterrey, Escuela Med & Ciencias Salud, Monterrey, Nuevo Leon, Mexico

Chavez-Canales, Maria:
 Univ Paris 06, Fac Med, INSERM, UMRS1155, Paris, France

 Univ Nacl Autonoma Mexico, Inst Invest Biomed, Translat Med Unit, Mexico City, DF, Mexico

 Inst Nacl Cardiol Ignacio Chavez, Mexico City, DF, Mexico

Ostrosky-Frid, Mauricio:
 Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Nephrol & Mineral Metab, Mexico City, DF, Mexico

 Univ Nacl Autonoma Mexico, Fac Med, PECEM, Mexico City, DF, Mexico

Rodriguez-Gama, Alejandro:
 Univ Nacl Autonoma Mexico, Mol Physiol Unit, Inst Invest Biomed, Mexico City, DF, Mexico

Vazquez, Norma:
 Univ Nacl Autonoma Mexico, Mol Physiol Unit, Inst Invest Biomed, Mexico City, DF, Mexico

 Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Nephrol & Mineral Metab, Mexico City, DF, Mexico

Gonzalez-Rodriguez, Xochiquetzal:
 Univ Nacl Autonoma Mexico, Dept Quim Analit, Fac Quim, Mexico City, DF, Mexico

Garcia-Valdes, Jesus:
 Univ Nacl Autonoma Mexico, Dept Quim Analit, Fac Quim, Mexico City, DF, Mexico

Hadchouel, Juliette:
 Univ Paris 06, Fac Med, INSERM, UMRS1155, Paris, France

Ellison, David:
 Oregon Hlth & Sci Univ, Dept Med, Div Nephrol & Hypertens, Portland, OR 97201 USA

 Vet Affairs Portland Hlth Care Syst, Portland, OR USA

Gamba, Gerardo:
 Univ Nacl Autonoma Mexico, Mol Physiol Unit, Inst Invest Biomed, Mexico City, DF, Mexico

 Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Nephrol & Mineral Metab, Mexico City, DF, Mexico

 Tecnol Monterrey, Escuela Med & Ciencias Salud, Monterrey, Nuevo Leon, Mexico
ISSN: 1931857X
Editorial
AMER PHYSIOLOGICAL SOC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA, Estados Unidos America
Tipo de documento: Article
Volumen: 315 Número: 3
Páginas: 734-745
WOS Id: 000444017300021
ID de PubMed: 29846116

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