WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4

Hypertension. 2014 Nov;64(5):1047-53. doi: 10.1161/HYPERTENSIONAHA.114.04036. Epub 2014 Aug 11.


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.

Keywords: Xenopus laevis; familial hypertensive hyperkalemia; hypertension, renal; kidney tubules, distal; mice, knockout; pseudohypoaldosteronism, type II; water-electrolyte balance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / physiology
  • Disease Models, Animal
  • Female
  • Humans
  • In Vitro Techniques
  • Kidney / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Minor Histocompatibility Antigens
  • Phenotype
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / physiology*
  • Pseudohypoaldosteronism / physiopathology
  • Signal Transduction / physiology*
  • Sodium Chloride Symporters / physiology*
  • WNK Lysine-Deficient Protein Kinase 1


  • Minor Histocompatibility Antigens
  • Sodium Chloride Symporters
  • Prkwnk4 protein, mouse
  • Stk39 protein, mouse
  • Protein Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • Wnk1 protein, mouse