NYMC Faculty Publications

The Cyp2c44 Epoxygenase Regulates Epithelial Sodium Channel Activity and the Blood Pressure Responses to Increased Dietary Salt

Author Type(s)

Faculty

DOI

10.1074/jbc.M113.508416

Journal Title

The Journal of Biological Chemistry

First Page

4377

Last Page

4386

Document Type

Article

Publication Date

2-14-2014

Department

Pharmacology

Keywords

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

Disciplines

Medicine and Health Sciences

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.

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