In addition, the increased activity of sterol regulatory element-binding protein-1 and carbohydrate regulatory element binding protein-1 and decreased activity of phosphorylated acetyl-CoA carboxylase most likely also play a role in increased free fatty acid synthesis and accumulation of triglycerides in diabetic kidney disease and PPARa activation can suppress the SREBP pathway through the reduction of liver X receptor /retinoid X receptor formation in the liver. PGC-1a functionally interacts with transcriptional factors, particularly with members of nuclear receptor families such as PPARa, PPARc, ERR-1a, LXR and hepatocyte nuclear factor-4 a, although also with non-nuclear receptor transcription factors and regulatory elements including the cAMP response element-binding protein and SREBP-1c. These diverse members of the nuclear receptor superfamily, such as PPARa, PPARc, and ERR-1a, improve hepatic lipogenesis via suppression of the lipogenic transcription factor SREBP-1c. PGC-1a targets ERR-1a, which serves as an internal ‘amplifier’ of the PGC1a cascade and is an important regulator of mitochondrial energy transduction pathways, including fatty acid oxidation and oxidative phosphorylation. In addition, PGC-1a regulates class O forkhead box 3a, which is a direct transcription regulator of a group of oxidative protection genes in primary endothelial cells. FoxO3a and PGC-1a interact directly and cooperatively; their interaction regulates mitochondrial oxidative stress. We have previously reported that PPARa deficiency appears to aggravate the severity of diabetic nephropathy through increase in extracelluar matrix formation, inflammation and circulating FFA and TG concentrations. We also demonstrated that fenofibrate ameliorated diabetic nephropathy directly, which may go beyond a systemic lipid-lowering effect, as evidenced by improvements in albuminuria, glomerular hypertrophy and mesangial expansion in a type 2 diabetic model. However, the underlying mechanisms responsible for the beneficial effect of fenofibrate on diabetic nephropathy are not completely understood. We hypothesized that fenofibrate can potentially improve renal lipotoxicity-induced oxidative stress and apoptosis by way of the activation of AMPKPGC-1a-ERR-1a and its downstream PI3K-Akt-FoxO3a pathway. This study demonstrates that diabetic nephropathy is associated with an increase in renal lipid accumulation, apoptotic renal injury and oxidative stress which are related to a decreased level of PPARa expression in diabetic mice. These changes lead to the inactivation of AMPK-PGC-1a-ERR-1a signaling and the deregulation of their target molecules, SREBP-1, ChREBP-1 and PI3KAkt-FoxO3a, which subsequently result in an increase in oxidative stress in the kidney. On the contrary, fenofibrate ameliorates diabetic nephropathy by way of the activation of AMPK-PGC-1aERR-1a signaling and the subsequent.