Faculty Collaboration Database

The Cyp2c44 epoxygenase regulates epithelial sodium channel activity and the blood pressure responses to increased dietary salt. J Biol Chem 2014 Feb 14;289(7):4377-86

Date

12/26/2013

Pubmed ID

24368771

Pubmed Central ID

PMC3924300

DOI

10.1074/jbc.M113.508416

Scopus ID

2-s2.0-84894174832 (requires institutional sign-in at Scopus site)   48 Citations

Abstract

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 pressure of hypertensive Cyp2c44(-/-) mice identifies a role for the channel in the hypertensive phenotype of the animals. These studies: (a) identify an antihypertensive role for the kidney Cyp2c44 epoxygenase and for its epoxyeicosatrienoic acid (EET) 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 γ 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.

Author List

Capdevila JH, Pidkovka N, Mei S, Gong Y, Falck JR, Imig JD, Harris RC, Wang W

MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Cytochrome P-450 Enzyme System
Cytochrome P450 Family 2
Epithelial Sodium Channels
Humans
Hypertension
Kidney
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase 3
Phosphorylation
Sodium Chloride, Dietary