Combination of PPAR-α Agonist and DPP-4 Inhibitor: A Novel Therapeutic Approach in the Management of Diabetic Nephropathy

Abstract

The present study investigated the combined effect of fenofibrate (PPAR-α agonist) and saxagliptin (DPP-4 inhibitor) in diabetes-induced experimental nephropathy. Rats were administered streptozotocin (STZ) (55 mg/ kg i.p., once) to induce experimental diabetes mellitus. The development of diabetic nephropathy was assessed biochemically and histologically. In addition, the diabetes-induced lipid profile and renal oxidative stress were assessed. The single administration of STZ produced diabetes, which induced renal oxidative stress, altered the lipid profile and subsequently produced nephropathy in 8 weeks by increasing serum creatinine, blood urea nitrogen, proteinuria, and glomerular damage. Treatment with fenofibrate (30 mg/kg/day p.o.) normalized the altered lipid profile in diabetic rats, whereas the saxagliptin (3 mg/kg p.o.) treatment has no effect on lipid alteration in diabetic rats. Treatment with saxagliptin partially reduces the elevated glucose levels in diabetic rats, whereas fenofibrate treatment has no effect on it. The combination of fenofibrate and saxagliptin was more effective in attenuating the diabetes-induced nephropathy and renal oxidative stress as compared to treatment with either drug alone or lisinopril (1 mg/kg/day p.o.) (a standard agent). It may be concluded that diabetes-induced oxidative stress and lipid alterations may be responsible for the induction of nephropathy in diabetic rats. The concurrent administration of fenofibrate and saxagliptin may have prevented the development of diabetes-induced nephropathy by reducing the lipid alteration, decreasing the renal oxidative stress and providing the direct nephroprotective action.