DPP-4 inhibitor sitagliptin prevents inflammation and oxidative stress of heart and kidney in two kidney and one clip (2K1C) rats

Abstract

Background: Hyperglycemia and insulin resistance often develop cardiovascular and nephrological dysfunction in diabetic patients. Sitagliptin is used to treat diabetes and showed potential benefit in lowering increased blood glucose level in diabetes. This investigation reports the effect of sitagliptin treatment on oxidative stress in kidney and heart of 2K1C rats. Methods: Male Long Evans rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2K1C) method]. These animals entered a 4-weeks dosing period with sitagliptin. Blood and urine sampling and organ harvesting were finally performed. Blood plasma, heart, kidney tissues and urine were tested for the assessment of inflammation and oxidative stress in kidney and heart of 2K1C rats after 4 weeks of surgery. Results: 2K1C rats showed cardiac hypertrophy, increased left ventricular wet weight compared to sham which was not significantly altered by sitagliptin treatment. Uric acid and creatinin concentrations were also increased in 2K1C rats. Sitagliptin significantly prevented the elevation of uric acid and creatinin concentration in plasma and urine in this rat model. Oxidative stress markers in plasma such as malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) concentrations were increased in the 2K1C rats as compared to sham-operated animals. Increased concentrations of these oxidative stress markers were also normalized by sitagliptin treatment. 2K1C rats also showed increased level of uric acid and creatinine both in plasma and urine; which are also reduced to normal level in sitagliptin treated rats. Moreover, 2K1C surgery initiated inflammatory cell infiltration, increased MPO activity and fibrosis in both heart and kidneys which were further ameliorated by sitagliptin treatment. Conclusion: Our study suggests that sitagliptin treatment in 2K1C rats prevented inflammation and fibrosis of heart and kidney by ameliorating elevated oxidative stress in heart and kidney tissues.