Document Detail


The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt.
MedLine Citation:
PMID:  24368771     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Hypertension is a major risk factor for cerebral, cardiovascular, and renal disease and its prevalence and devastating consequences raises a need for new strategies for its early diagnosis and treatment. We show here that lack of a Cyp2c44 epoxygenase causes dietary salt sensitive hypertension, a common form of the human disease. Cyp2c44(-/-) mice on normal salt diets are normotensive but become hypertensive when fed high salt. Hypertensive Cyp2c44(-/-) mice show a hyperactive kidney epithelial sodium channel (ENaC) and reductions in ERK1/2 and ENaC subunit phosphorylation. The demonstration that Amiloride, an ENaC inhibitor, lowers the blood pressures of hypertensive Cyp2c44(-/-) mice identifies a role for the channel in the animals hypertensive phenotype. These studies: a) identify an anti-hypertensive role for the kidney Cyp2c44 epoxygenase, and for its epoxyeicosatrienoic acids (EETs) metabolites in the in vivo control of ENaC activity, and the activation of mitogenic kinase pathways, b) provide evidence for a Cyp2c44 epoxygenase, EET-mediated, mechanism of ENaC regulation involving an ERK1/2-catalyzed threonine phosphorylation of the channel gamma subunit, and c) characterize a common scientific platform that could explain the seemingly unrelated biological activities attributed to the epoxygenase metabolites in cell proliferation, angiogenesis, channel activity, and blood pressure control. It is expected that these results will serve as a basis for the development of novel strategies for the early diagnosis and treatment of hypertension and of pathophysiologies associated with dysfunctional mitogenic signaling.
Authors:
Jorge H Capdevila; Nataliya Pidkovka; Shaojun Mei; Yan Gong; John R Falck; John D Imig; Raymond C Harris; Wenhui Wang
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-12-24
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  -     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Dec 
Date Detail:
Created Date:  2013-12-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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