title: Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature.
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.
authors.affiliation: Department of Pharmacology, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Park
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Soo-Kyoung
authors.initials: SK
authors.lastname: Choi
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zeng
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D001808:Blood Vessels / Q000166:cytology / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050052:TRPC Cation Channels / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C499025:Wnk4 protein, rat; D017346:Protein Serine-Threonine Kinases