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

Authors
 Hyun Woo Park  ;  Joo Young Kim  ;  Soo-Kyoung Choi  ;  Young-Ho Lee  ;  Weizhong Zeng  ;  Kyung Hwan Kim  ;  Shmuel Muallem  ;  Min Goo Lee 
Citation
 Proceedings of the National Academy of Sciences of the United States of America, Vol.108(26) : 10750-10755, 2011 
Journal Title
 Proceedings of the National Academy of Sciences of the United States of America 
ISSN
 0027-8424 
Issue Date
2011
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
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/93495
DOI
10.1073/pnas.1104271108
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실)
Yonsei Authors
김경환(Kim, Kyung Hwan) ; 김주영(Kim, Joo Young) ; 박현우(Park, Hyun Woo) ; 이민구(Lee, Min Goo) ; 이영호(Lee, Young Ho) ; 최수경(Choi, Soo Kyoung)
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