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Regulation of Cardiovascular Functions by Eicosanoids and Other Lipid Mediators

PPAR- activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats

¹Vascular Biology Center and Departments of ²Pharmacology and Toxicology and of ³Physiology, Medical College of Georgia, Augusta, Georgia

Submitted 31 August 2005 ; accepted in final form 21 February 2006

Previous studies have shown that the synthesis of renal cytochrome P-450 (CYP)-derived eicosanoids is downregulated in genetic or high-fat diet-induced obese rats. Experiments were designed to determine whether fenofibrate, a peroxisome proliferator-activated receptor (PPAR)- agonist, would induce renal eicosanoid synthesis and improve endothelial function in obese Zucker rats. Administration of fenofibrate (150 mg·kg^–1·day^–1 for 4 wk) significantly reduced plasma insulin, triglyceride, and total cholesterol levels in obese Zucker rats. CYP2C11 and CYP2C23 proteins were downregulated in renal vessels of obese Zucker rats. Consequently, renal vascular epoxygenase activity decreased by 15% in obese Zucker rats compared with lean controls. Chronic fenofibrate treatment significantly increased renal cortical and vascular CYP2C11 and CYP2C23 protein levels in obese Zucker rats, whereas it had no effect on epoxygenase protein and activity in lean Zucker rats. Renal cortical and vascular epoxygenase activities were consequently increased by 54% and 18%, respectively, in fenofibrate-treated obese rats. In addition, acetylcholine (1 µM)-induced vasodilation was significantly reduced in obese Zucker kidneys (37% ± 11%) compared with lean controls (67% ± 9%). Chronic fenofibrate administration increased afferent arteriolar responses to 1 µM of acetylcholine in obese Zucker rats (69% ± 4%). Inhibition of the epoxygenase pathway with 6-(2-propargyloxyphenyl)hexanoic acid attenuated afferent arteriolar diameter responses to acetylcholine to a greater extent in lean compared with obese Zucker rats. These results demonstrate that the PPAR- agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats.

kidney; cytochrome P-450; metabolic syndrome; renal vessels; peroxisome proliferator-activated receptor-

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