We investigated the effects of a high-fat (HF) diet and peroxisome proliferator-activated receptor (PPAR)-alpha activation on the intrarenal lipotoxicity associated with the renin-angiotensin system (RAS) and oxidative stress using spontaneously hypertensive (SHR) rats. Male SHR and Wistar-Kyoto (WKY) rats at 8 weeks of age were fed either a normal-fat diet or an HF diet without or with fenofibrate treatment for 12 weeks. Severe intrarenal lipid accumulation was noted in the SHR rats fed an HF diet than in WYK rats fed an HF diet (P<0.05). This lipid accumulation was associated with a 70% decrease in renal PPARalpha expression in SHR rats, whereas an HF diet increased the expression of PPARalpha in WKY rats by threefold. An HF diet also activated intrarenal, not systemic, RAS and induced oxidative stress associated with reduced nitric oxide (NO) bioavailability. By contrast, fenofibrate attenuated weight gain, fat mass and insulin resistance. Fenofibrate recovered HF diet-induced decreases in intrarenal PPARalpha expression and fat accumulation, and abolished intrarenal RAS activation and oxidative stress in SHR-HF animals (P<0.01). These activities conferred protection against increased blood pressure (BP), glomerulosclerosis and renal inflammation. Intrarenal free fatty acid and triglyceride concentrations were positively correlated with angiotensin II (gamma=0.63, 0.36) and 24-h urinary 8-hydroxy-deoxyguanosine (gamma=0.36, 0.39), and negatively correlated with PPARalpha contents (gamma=-0.47, -0.44; P<0.05). An HF diet-induced lipotoxicity by depletion of intrarenal PPARalpha aggravated BP and renal inflammation as a result of intrarenal RAS activation and oxidative stress. Therefore, intervention with PPARalpha activators can effectively prevent diet-induced renal lipotoxicity in hypertensive rats.