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

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


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 WNK4CD25-/- 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.

Original languageEnglish (US)
Pages (from-to)1047-1053
Number of pages7
Issue number5
StatePublished - Nov 1 2014


  • Distal
  • Familial hypertensive hyperkalemia
  • Hypertension, renal
  • Kidney tubules
  • Knockout
  • Mice
  • Pseudohypoaldosteronism/
  • Type II
  • Water-electrolyte balance
  • Xenopus laevis

ASJC Scopus subject areas

  • Internal Medicine


Dive into the research topics of 'WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4'. Together they form a unique fingerprint.

Cite this