Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

Abstract

Previous studies have indicated that the production of 20-hydroxyecisatatraenoic acid (20-HETE) is similar in the liver of C57/B6 mice and rats, but the renal production of 20-HETE is very low in this strain of mice. The present study examined the effects of induction of the renal production of 20-HETE with fenofibrate (FF) on the development of angiotensin II (Ang II)–dependent hypertension in C57BL/6J mice. The mice were divided into 4 groups and treated with vehicle (control), FF (90 mg/kg per day, IP), Ang II (1000 ng/kg per minute, SC), and Ang II plus FF. Mean arterial blood pressure (MAP) averaged 109±4 and 106±2 mm Hg in control and FF-treated mice (n=7). MAP was significantly increased in the Ang II-treated mice to 144±4 mm Hg (n=7). However, FF treatment prevented the development of Ang II–dependent hypertension, with MAP averaging 115±5 mm Hg in mice treated with both Ang II plus FF (n=7). Renal production of 20-HETE was very low in control (n=7) and Ang II-treated (n=7) mice and was increased by >2-fold in FF-treated (n=7) and Ang II plus FF-treated (n=7) mice. The levels of Cyp4A proteins were markedly increased in the kidneys of mice treated with FF and Ang II plus FF but not in the renal vasculature. These results suggest that upregulation of the production of 20-HETE in renal tubules may contribute to the blood pressure-lowering effects of FF treatment in Ang II–dependent hypertension in C57BL/6J mice.