ABSTRACT
BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-gamma is a member of the nuclear receptor superfamily. PPAR-gamma plays an important role in numerous cellular processes including adipogenesis, insulin sensitivity, cell cycle progression, cell differentiation, inflammation, and extracellular matrix production. This study investigated the effect of a PPAR-gamma agonist on the progression of diabetic nephropathy in OLETF rats. METHODS: 30 week-old male OLETF rats were treated for 10 weeks as follows:diabetic control (DM), no treatment:pioglitazone therapy (DM+Pio). LETO rats were used as non-diabetic control (control). Body weight, blood pressure, blood sugar, creatinine, total cholesterol, triglyceride, and urinary protein excretion were measured. Histological analysis was taken with light microscope. Glomerular protein and mRNA expression of transforming growth factor (TGF)-beta1 and fibronectin were estimated by Western blot and RT-PCR. Kidney sections were stained for fibronectin by immunohistochemistry. RESULTS: Serum glucose, triglyceride and urinary protein excretion were decreased in DM+Pio rats compared to DM rats (p<0.05). PAS staining showed glomerular hypertrophy, mesangial expansion, nodular sclerosis, and glomerular basement membrane thickening in glomeruli of DM rats, but these changes were attenuated in glomeruli of pioglitazone-treated rats. Treatment with pioglitazone resulted in a significant decrease in TGF-beta1 protein and mRNA expression in diabetic glomeruli (80.6% and 78.4%, respectively). Glomerular expression of fibronectin protein and mRNA were also decreased in pioglitazone treatment group compared with DM group (93.1% and 98.6%, respectively). Immunohistochemical staining for fibronectin showed similar results. CONCLUSION: Increased TGF-beta1 and fibronectin mRNA and protein expressions in diabetic rat glomeruli were significantly ameliorated by pioglitazone treatment. These data suggest that activation of PPAR-gamma may play an important role in prevention and treatment of diabetic nephropathy.