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

Hyun Woo Park, Joo Young Kim, Soo Kyoung Choi, Young Ho Lee, Weizhong Zeng, Kyung Hwan Kim, Shmuel Muallem, Min Goo Lee

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)10750-10755
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number26
DOIs
Publication statusPublished - 2011 Jun 28

All Science Journal Classification (ASJC) codes

  • General

Fingerprint Dive into the research topics of 'Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature'. Together they form a unique fingerprint.

  • Cite this