2. Academic Validation
  3. Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC

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

  • Am J Physiol Renal Physiol. 2018 Sep 1;315(3):F734-F745. doi: 10.1152/ajprenal.00145.2018.
Eduardo R Argaiz 1 2 3,  Maria Chavez-Canales 4 5,  Mauricio Ostrosky-Frid 2 6,  Alejandro Rodríguez-Gama 1,  Norma Vázquez 1 2,  Xochiquetzal Gonzalez-Rodriguez 7,  Jesus Garcia-Valdes 7,  Juliette Hadchouel 4,  David Ellison 8 9,  Gerardo Gamba 1 2 3
Affiliations

Affiliations

  • 1 Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Tlalpan, Mexico City, Mexico.
  • 2 Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan Mexico City, Mexico.
  • 3 Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo León , Mexico.
  • 4 INSERM UMRS1155, University Pierre and Marie Curie, Faculty of Medicine , Paris , France.
  • 5 Translational Medicine Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cardiología Ignacio Chávez, Tlalpan, México City, Mexico.
  • 6 PECEM, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacan, Mexico City, Mexico.
  • 7 Departamento de Química Analítica, Facultad de Química, Universidad Nacional Autónoma de México, Coyoacan, Mexico City, Mexico.
  • 8 Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University , Portland, Oregon.
  • 9 Veterans Affairs Portland Health Care System, Portland, Oregon.
PMID: 29846116 DOI: 10.1152/ajprenal.00145.2018
Abstract

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.

Keywords

Na+:Cl− cotransporter; STE20-proline-alanine rich kinase; distal convoluted tubule; diuretics; salt transport.

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