title: The Cyp2c44 epoxygenase regulates epithelial sodium channel activity and the blood pressure responses to increased dietary salt.
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.
authors.affiliation: From the Department of Medicine, Vanderbilt University, Nashville Tennessee 37232.
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Capdevila
authors.forename: Nataliya
authors.initials: N
authors.lastname: Pidkovka
authors.forename: Shaojun
authors.initials: S
authors.lastname: Mei
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.forename: Wenhui
authors.initials: W
authors.lastname: Wang
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017673:Sodium Chloride, Dietary / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D053503:Epithelial Sodium Channels; D017673:Sodium Chloride, Dietary; D003577:Cytochrome P-450 Enzyme System; C492667:Cyp2c23 protein, mouse; D000072467:Cytochrome P450 Family 2; D048052:Mitogen-Activated Protein Kinase 3
keywords: EETs; ENaC; ERK; Epoxygenase Pathway; Hypertension; Natriuresis; Sodium Transport