PPAR-α activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats
Autor: | John D. Imig, Jeffrey E. Quigley, Yiqing Zhou, Mong Heng Wang, Jianghe Yuan, Xueying Zhao |
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Rok vydání: | 2006 |
Předmět: |
Male
medicine.medical_specialty Kidney Cortex Nitric Oxide Synthase Type III Cytochrome Endothelium Physiology Immunoblotting Kidney Weight Gain Cytochrome P-450 CYP2J2 Renal Circulation Cytochrome P-450 Enzyme System Fenofibrate Physiology (medical) Internal medicine medicine Animals Insulin PPAR alpha Obesity Hypolipidemic Agents Arachidonic Acid biology Reverse Transcriptase Polymerase Chain Reaction Chemistry Activator (genetics) Microcirculation nutritional and metabolic diseases medicine.disease Lipids Rats Rats Zucker Isoenzymes Vasodilation medicine.anatomical_structure Endocrinology Eicosanoid Dilator biology.protein Eicosanoids Endothelium Vascular Metabolic syndrome Cardiology and Cardiovascular Medicine medicine.drug |
Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 290:H2187-H2195 |
ISSN: | 1522-1539 0363-6135 |
Popis: | 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)-α agonist, would induce renal eicosanoid synthesis and improve endothelial function in obese Zucker rats. Administration of fenofibrate (150 mg·kg−1·day−1for 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-α agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats. |
Databáze: | OpenAIRE |
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