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首页> 外文期刊>American Journal of Physiology >PPAR-alpha activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats.
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PPAR-alpha activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats.

机译：PPAR-α活化剂非诺贝特在肥胖的Zucker大鼠中增加了肾脏CYP衍生的类花生酸的合成并改善了内皮舒张功能。

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摘要

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.
机译：先前的研究表明，在遗传或高脂饮食诱导的肥胖大鼠中，肾细胞色素P-450（CYP）衍生的类花生酸的合成被下调。设计实验以确定过氧化物酶体增殖物激活受体（PPAR）-α激动剂非诺贝特是否会诱导肥胖类Zucker大鼠中的肾类二十烷酸合成并改善其内皮功能。非诺贝特（150 mg.kg（-1）.day（-1）连续4周）的给药可显着降低肥胖Zucker大鼠的血浆胰岛素，甘油三酸酯和总胆固醇水平。肥胖Zucker大鼠肾脏血管中CYP2C11和CYP2C23蛋白表达下调。因此，与瘦对照组相比，肥胖的Zucker大鼠的肾血管环氧酶活性降低了15％。慢性非诺贝特治疗可显着增加肥胖Zucker大鼠的肾皮质和血管中CYP2C11和CYP2C23蛋白水平，而对瘦Zucker大鼠的环氧合酶蛋白和活性无影响。因此，在用非诺贝特治疗的肥胖大鼠中，肾皮质和血管环氧酶活性分别增加了54％和18％。此外，与瘦对照组（67％+/- 9％）相比，肥胖的祖克肾脏（37％+/- 11％）中乙酰胆碱（1 microM）诱导的血管舒张明显减少。长期服用非诺贝特可增加肥胖的Zucker大鼠对1 microM乙酰胆碱的传入小动脉反应（69％+/- 4％）。与瘦的Zucker大鼠相比，在瘦肉中用6-（2-炔丙基氧苯基）己酸抑制环氧酶的途径可更大程度地减弱对乙酰胆碱的传入小动脉直径反应。这些结果表明，在肥胖的Zucker大鼠中，PPAR-α激动剂非诺贝特增加了肾CYP衍生的类花生酸，并恢复了内皮舒张功能。

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