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

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

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)F734-F745
JournalAmerican Journal of Physiology - Renal Physiology
Issue number3
StatePublished - Sep 6 2018


  • Distal convoluted tubule
  • Diuretics
  • Na:Cl cotransporter
  • STE20-proline-alanine rich kinase
  • Salt transport

ASJC Scopus subject areas

  • Physiology
  • Urology


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