Abstract 250: 20-HETE is Increased and EETs are Decreased in the Renal Vasculature of a Rat Model of Polycystic Ovary Syndrome

Abstract

Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among women during their reproductive years. Enlarged ovaries containing numerous small cysts, elevated circulating androgens, modest increases in blood pressure, and insulin resistance, are among the main symptoms of PCOS. However, the mechanisms responsible for higher blood pressure have not been elucidated. We have characterized a rat model of PCOS, the hyperandrogenemic female (HAF) rat that exhibits characteristics of PCOS in women. The present study was performed to test the hypothesis that 20-HETE and EET levels and expression of the cytochrome P450 (CYP) 4A ω-hydroxylases are different in HAF and placebo rats. Dihydrotestosterone (DHT) (7.5 mg/90 days) or placebo pellets were implanted subcutaneously in female SD rats (n = 6/group) at 4 weeks of age. Kidneys were removed at 12 weeks of age, preglomerular vessels isolated, and 20-HETE, EETs, and ω-hydroxylase activity were measured by liquid chromatography-mass spectroscopy; CYP 4A protein was measured by western blot. The basal renal microvascular level of 20-HETE (0.15± 0.02 vs. 0.81± 0.08 pmol/mg; p<0.001) and renal vascular ω-hydroxylase activity (0.20± 0.04 vs. 0.69± 0.14 pmol/min/mg; p<0.01) were higher in HAF compared to placebo controls. In addition, CYP4A protein expression was increased by 79% (0.31 vs. 0.40 AU; p<0.005) in HAF rats. In contrast, the basal renal microvascular level of EETs was reduced in HAF rats (40.80± 11.96 vs. 2.33± 1.74 pmol/mg; p<0.005). The data suggest that renal production of 20-HETE is increased in HAF, and may contribute to renal vascoconstriction, whereas EETs are decreased which may contribute to reduced vasodilation of preglomerular vasculature. These data suggest that androgens may affect intrarenal vascular eicosanoids in women with PCOS to mediate their increases in blood pressure.