Fenofibrate improves renal function by amelioration of NOX-4, IL-18, and p53 expression in an experimental model of diabetic nephropathy

Among several pathological mechanisms involved in diabetic nephropathy, oxidative stress, inflammation, and apoptosis play a prominent role. Fenofibrate, a peroxisome proliferator-activated receptor- (PPAR-) agonist, has markedly improved oxidative stress and inflammatory responses, but there is no evidence about its effects on interleukin-18 (IL-18), NADPH oxidase type 4 (NOX-4), and p53 expression in diabetic kidneys. The aim of this study was to evaluate possible effects of fenofibrate on improving the underlying mechanisms of diabetic nephropathy. Male Wistar rats were randomly divided into four groups namely, normal, normal treated, diabetic and diabetic treated (N=6). Diabetes was induced by a single dose of streptozotocin (40mg/kg; IV). Treated animals received fenofibrate for 8 weeks daily (80mg/kg; po). All groups were sacrificed on day 56 and blood, urine, and tissue samples were collected. Serum levels of urea, uric acid, creatinine, and glucose were assessed. Then, serum levels of malondialdehyde (MDA), nitrate, and glutathione (GLT), as well as the activities of catalase (CAT) and superoxide dismutase (SOD) enzymes were measured. The expression level of NOX-4, IL-18, and p53 proteins at both mRNA and protein levels were evaluated. Diabetes significantly increased albuminuria, free radicals production, inflammation, and apoptosis in non-treated rats while lowered antioxidant capacity. Moreover, diabetes caused histological damages leading to renal failure. Treatment with fenofibrate improved renal function by improving creatinine clearance (P=0.01) and protein excretion (P=0.001) and lowering plasma levels of blood urea nitrogen (P=0.001), creatinine (P=0.001), and uric acid (P=0.01). Fenofibrate potentiated antioxidant defense systems by enhancing CAT (P=0.01) and SOD (P=0.01) enzymes activities and GLT content (P=0.01), and reduced oxidative damage by lowering MDA generation (P=0.02). Fenofibrate also attenuated the expression of NOX-4 (P=0.05), IL-18 (P=0.05), and p53 (P=0.05) at both mRNA and protein levels. In conclusion, treatment with fenofibrate improved renal function by suppression of oxidative stress, attenuation of inflammation, and inhibition of apoptosis.