PPAR-alpha activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats.
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.
Zhao
Xueying
X
Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500. xzhao@mail.mcg.edu
Quigley
Jeffrey E
JE
Yuan
Jianghe
J
Wang
Mong-Heng
MH
Zhou
Yiqing
Y
Imig
John D
JD
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015777:Eicosanoids / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000187:drug effects*; D011345:Fenofibrate / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D015151:Immunoblotting; D007328:Insulin / Q000097:blood; D007527:Isoenzymes / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000503:physiopathology*; D047493:PPAR alpha / Q000819:agonists*; D051381:Rats; D011924:Rats, Zucker; D012079:Renal Circulation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D015430:Weight Gain / Q000187:drug effects
C000717351:Cyp2c23 protein, rat; D015777:Eicosanoids; D000960:Hypolipidemic Agents; D007328:Insulin; D007527:Isoenzymes; D008055:Lipids; D047493:PPAR alpha; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D052250:Nitric Oxide Synthase Type III; D000090762:Cytochrome P-450 CYP2J2; D011345:Fenofibrate