PPAR-alpha agonist fenofibrate induces renal CYP enzymes and reduces blood pressure and glomerular hypertrophy in Zucker diabetic fatty rats.

摘要

We have previously shown that fenofibrate, a peroxisome proliferator-activated receptor-alpha activator, increases renal cytochrome P450 (CYP)-derived eicosanoids and improves endothelial function in pre-diabetic obese rats. The present study was designed to explore the efficacy of fenofibrate on blood pressure and renal injury in the advanced stage of type-2 diabetes. 26-week-old male Zucker diabetic fatty rats (ZDF) were fed fenofibrate (100 mg/kg/day) for 6 weeks. Chronic treatment with fenofibrate normalized systolic blood pressure and reduced glomerular size by 19% in diabetic rats. Western blot and fluorescent immunostaining revealed that the over-expression of collagen type IV and alpha-smooth muscle actin was significantly attenuated in the kidney of fenofibrate-treated ZDF (F-ZDF) rats. In addition, fenofibrate administration dramatically decreased the cyclin D1 protein level in the kidney of diabetic rats. In contrast, renal CYP2C23 and CYP4A proteins were significantly increased in F-ZDF rats. These fenofibrate effects were observed in the absence of significant changes in glucose, insulin or lipid levels. Taken together, our results demonstrate that fenofibrate may lower blood pressure and attenuate glomerular hypertrophy and collagen accumulation through the downregulation of cyclin D1 and upregulation of CYP monooxygenases in the late stage of type-2 diabetes.