Abstract 355: Mineralocorticoid Receptor Activation Alters Epoxyeicosatrienoic Acid Production In Vivo

Abstract

Epoxyeicosatrienoic acids (EETs) are products of CYP450 epoxygenase and are degraded to DHETs by soluble epoxide hydrolase (sEH). Their natriuretic and vasodilatory actions oppose those of mineralocorticoids, but the effect of aldosterone on EET metabolism has not been investigated. To test the hypothesis that aldosterone impairs EET metabolism via altered production or degradation, we treated wild type C57Bl6J mice with aldosterone (50 μg/kg/d) or vehicle ± the mineralocorticoid receptor (MR) antagonist RU-28318 during high sodium intake for 2 weeks. Aldosterone decreased plasma ( Fig A ; -29%, 4.4±0.6 vs. 3.1±0.4 ng/ml, control vs. aldosterone) and pancreatic EETs ( Fig B ;-43%, 112±15 vs. 64±15 ng/mg tissue, control vs. aldosterone) but not hepatic or kidney EETs. MR antagonism prevented this effect of aldosterone on plasma EETs. The urinary DHET/EET ratio markedly increased, suggesting increased renal sEH activity. Because both aldosterone and EETs affect insulin secretion, we further assessed CYP epoxygenase expression within the pancreas. We detected Cyp2c44 and sEH ( Ephx2) mRNA in isolated murine islets, and immunohistochemistry demonstrated CYP2C expression in beta-cells. Aldosterone decreased protein expression of CYP2C epoxygenase within whole pancreas, and ex vivo aldosterone treatment decreased Cyp2c and increased sEH mRNA expression within isolated islets. These data demonstrate that aldosterone decreases CYP2C expression and EET production in vivo . We propose that the renin-angiotensin-aldosterone system interacts with the CYP450 epoxygenase system to alter blood pressure and glucose homeostasis via EET metabolism.