Given the role of PPARα played in the regulation of PI3K/AKT and ERK/MAPK signaling, we therefore sought to more closely investigate the renoprotective effect of PPARa agonist, fenofibrate, in diabetic nephropathy by (1) determining its inhibition of glucose-induced mesangial cell proliferation and extracellular matrix accumulation; (2) examining its anti-proliferative and anti-ECM-secreting effects by an inhibitory effect of both the phosphorylation and activity of PI3K/AKT and ERK1/2 signaling pathways. This evidence concerns the gene MAPK3 and diabetic kidney disease.