PPAR-alpha activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats. Am J Physiol Heart Circ Physiol 2006 Jun;290(6):H2187-95
Date
02/28/2006Pubmed ID
16501022DOI
10.1152/ajpheart.00937.2005Scopus ID
2-s2.0-33744940507 (requires institutional sign-in at Scopus site) 51 CitationsAbstract
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)-alpha 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 microM)-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 microM 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-alpha agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats.
Author List
Zhao X, Quigley JE, Yuan J, Wang MH, Zhou Y, Imig JDMESH terms used to index this publication - Major topics in bold
AnimalsArachidonic Acid
Cytochrome P-450 Enzyme System
Eicosanoids
Endothelium, Vascular
Fenofibrate
Hypolipidemic Agents
Immunoblotting
Insulin
Isoenzymes
Kidney
Kidney Cortex
Lipids
Male
Microcirculation
Nitric Oxide Synthase Type III
Obesity
PPAR alpha
Rats
Rats, Zucker
Renal Circulation
Reverse Transcriptase Polymerase Chain Reaction
Vasodilation
Weight Gain