Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature

Proc Natl Acad Sci U S A. 2011 Jun 28;108(26):10750-5. doi: 10.1073/pnas.1104271108. Epub 2011 Jun 13.

Abstract

Mutations in the serine-threonine kinase with-no-lysine 4 (WNK4) cause pseudohypoaldosteronism type 2 (PHAII), a Mendelian form of human hypertension. WNK4 regulates diverse ion transporters in the kidney, and dysregulation of renal transporters is considered the main cause of the WNK4 mutation-associated hypertension. Another determinant of hypertension is vascular tone that is regulated by Ca(2+)-dependent blood vessel constriction. However, the role of WNK4 in vasoconstriction as part of its function to regulate blood pressure is not known. Here, we report that WNK4 is a unique modulator of blood pressure by restricting Ca(2+) influx via the transient receptor potential canonical 3 (TRPC3) channel in the vasculature. Loss of WNK4 markedly augmented TRPC3-mediated Ca(2+) influx in vascular smooth muscle cells (VSMCs) in response to α-adrenoreceptor stimulation, which is the pathological hallmark of hypertension in resistance arteries. Notably, WNK4 depletion induced hypertrophic cell growth in VSMCs and increased vasoconstriction in small mesenteric arteries via TRPC3-mediated Ca(2+) influx. In addition, WNK4 mutants harboring the Q562E PHAII-causing or the D318A kinase-inactive mutation failed to mediate TRPC3 inhibition. These results define a previously undescribed function of WNK4 and reveal a unique therapeutic target to control blood pressure in WNK4-related hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / physiology*
  • Blood Vessels / cytology
  • Blood Vessels / physiology*
  • Cell Line
  • Humans
  • Mutation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • TRPC Cation Channels / physiology*
  • Vasoconstriction / physiology

Substances

  • TRPC Cation Channels
  • TRPC3 cation channel
  • Wnk4 protein, rat
  • Protein-Serine-Threonine Kinases