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Background and Aim. Diabetes mellitus is associated with an induction of vascular endothelial dysfunction (VED) that leads to the pathogenesis of diabetic nephropathy (DN). Diabetic nephropathy (DN) is a main cause of end stage renal disease. This study was designed to investigate the protective effects of irbesartan (IRB) and its combination with pioglitazone (PIO) on impaired endothelial dysfunction, oxidative stress, and inflammation beyond blood glucose control in streptozotocin- (STZ-) induced diabetic nephropathy in rats. Materials and Methods. Forty-eight male albino rats were divided equally and randomly into six groups: A (control non- diabetic non-treated) and B (diabetic non-treated) injected intraperitoneally by streptozotocin (65mg/kg) and nicotinamide (110 mg/kg) to induce diabetic nephropathy; C (diabetic treated with IRB (30mg/kg/daily) orally), D (diabetic treated with PIO (30mg/kg/daily) orally), E (diabetic treated with IRB and PIO in doses (30 mg/kg/day and 30 mg/kg/day) orally), and F (diabetic treated with IRB and PIO in doses (5mg/kg/day and 15mg/kg/day, resp.) orally for 12 weeks). Fasting blood glucose, urea, creatinine, albumin in urine levels, IL-6, nitric oxide (NO), and Malondialdehyde peroxidase (MDA) were determined in serum of the different groups at the end of the experiment; renal blood flow and aortic and renal histopathological changes were also evaluated. Results. Administration of irbesartan and pioglitazone to diabetic rats caused significant decrease in levels of urea, creatinine, albumin, serum inflammatory mediators (IL-6 and NO), and oxidative stress markers. The effects of irbesartan and/or pioglitazone were associated with improvement of renal blood flow, and they markedly reduced vascular and renal damage induced by diabetes. Conclusion. The results of the present study support the fact that the combination between irbesartan and pioglitazone was better than monotherapy on endothelial dysfunction and diabetic nephropathy through inhibition of the pro-inflammatory mediators, NO bioavailability, and oxidative stress, which are independent of their glucose-lowering properties. And there was no significant difference between the combination of pioglitazone and irbesartan in large doses and in low doses.

Effects of Pioglitazone and Irbesartan on Endothelial Dysfunction on Experimentally Streptozotocin-Induced Diabetic Nephropathy in Rats