Elsevier

Regulatory Peptides

Volume 166, Issues 1–3, 17 January 2011, Pages 48-54
Regulatory Peptides

Sitagliptin protects renal ischemia reperfusion induced renal damage in diabetes

https://doi.org/10.1016/j.regpep.2010.08.007Get rights and content

Abstract

This study was designed to investigate the possible effect of sitagliptin on renal damage induced by renal ischemia reperfusion (I/R) in diabetic rats. T2DM in rats was induced by the administration of nicotinamide (230 mg/kg, i.p.), 15 min prior to a single dose of streptozotocin (65 mg/kg, i.v.). In vivo renal I/R was performed in both T2DM and normal rats. Each protocol comprised ischemia for 30 min followed by reperfusion for 24 h and a treatment period of 14 days before induction of ischemia. Sitagliptin treated diabetic rats that underwent renal I/R demonstrated significant decrease in the serum concentrations of aspartate aminotransferase (p < 0.01), urea nitrogen (p < 0.01) and creatinine (p < 0.001) compared to renal I/R in diabetic rats. Lipid peroxidation, xanthine oxidase activity, myeloperoxidase activity and nitric oxide level in renal tissue were significantly (p < 0.05, p < 0.001, p < 0.01, p < 0.05 respectively) decreased after renal I/R in sitagliptin treated rats compared to diabetic rats. Antioxidant enzymes like glutathione (p < 0.05), glutathione peroxidase (p < 0.001), superoxide dismutase (p < 0.05) and catalase (p < 0.001) were significantly increased after renal I/R in sitagliptin treated diabetic rats compared to non treated diabetic rats. The typical DNA laddering was observed when renal I/R performed in diabetic rats, which indicates cell apoptosis. Sitagliptin treated rats demonstrated a decrease in DNA fragmentation and apoptosis. Furthermore, renal histopathology preserved in sitagliptin treated rats verified protection against renal I/R in diabetes. The results of present investigation established sitagliptin treatment attenuated renal damage induced by renal I/R in diabetic rats.

Research Highlights

►Sitagliptin treated rat demonstrated reduction in oxidative stress. ►Sitagliptin treatment caused modification in inflammatory process. ►Sitagliptin treatment found to decrease DNA fragmentation in diabetic rats. ►In conclusion sitagliptin treatment attenuated renal I/R in diabetic rats. ►The prevention shown via nitric oxide generation and neutrophil sequestration.

Introduction

The mechanisms responsible for the enhanced inflammatory response in type 2 diabetes (T2DM) and its contribution to the severe renal ischemia/reperfusion (I/R) injury observed in the T2DM kidney are unclear [1], [2]. Reactive oxygen species (ROS) and nitric oxide (NO) play an important role in mediating cell damage during I/R injury [3], [4]. Inflammation contributes substantially to the pathogenesis of I/R with a central role for particular cells, adhesion molecules, and cytokines [5]. Neutrophils are the inflammatory cells that produce high levels of ROS during I/R injury. Myeloperoxidase (MPO) is found in neutrophils and is found to catalyze the formation of hypochlorous acid (HOCl), a toxic agent to cellular components, which initiates oxidative injury [6]. Diabetic patients may need renal transplantation in their later life due to diabetic nephropathy. I/R injury is one of the dangerous complications of this procedure. Short period of ischemia (30 min) in diabetes has been demonstrated to reversible renal failure, leading to progressive injury with end stage renal disease [7]. Streptozotocin induced diabetes in rats increased renal sensitivity to I/R injury [1], [2], and that is why in this study we used diabetic rat for induction of renal I/R injury.

Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor represent a new class of antidiabetic agents reflecting their ability to extend the biological effects of incretin hormones like Glucagon-like peptide-1 (GLP-1) [8], [9], [10]. GLP-1 is one of the best studied incretin hormones [11], [12], [13], exerts insulinotropic and insulinomimetic properties via the G-protein-coupled, GLP-1 receptor, which has been reported to be expressed in renal tissue [14]. GLP-1 reported for its efficacy in I/R injury [15], [16], [17]. So we hypothesized via potentiating endogenous GLP-1 effect through sitagliptin, could improve renal damage induced by renal I/R, and therefore the present study was designed to investigate the effect of sitagliptin on renal I/R in diabetic rat.

Section snippets

Experimental groups and surgical procedure

Healthy adult Wistar rats (both sexes) weighing 200–250 g were used for this experiment whose protocol described herein was approved by the Institutional Animal Ethics Committee (IAEC) of Smt. R.B.P.M.C. Atkot. Permission was obtained from the committee for the purpose of control and supervision of experiments on Animals (CPCSEA), Ministry of Social Justice and Empowerment, Government of India. The rats were assigned to five different groups. Group-1 (n = 5): Normal sham-operated (underwent all

Effect of sitagliptin on renal function

Diabetic animals that underwent renal I/R, exhibited significant increase in the serum concentrations of AST, urea nitrogen and creatinine when compared with diabetic sham-operated animals (p < 0.001), suggesting a significant degree of glomerular dysfunction after induction of renal I/R. Serum concentrations of AST, urea nitrogen and creatinine were also significantly different in between RI/R group and DM + RI/R group (p < 0.001, p < 0.05, p < 0.001 respectively). Sitagliptin treatment exhibited

Discussion

Important question of this investigation is why probing effects of sitagliptin against renal I/R by using diabetic rats. Several possible explanations exist: i) the increased sensitivity to I/R could be due to hyperglycemia per se, and sitagliptin reported to control hyperglycemia, ii) secondary effects of hyperglycemia such as the increased oxidative stress, inflammatory response, and formation of NO could also be involved in renal injury induced by renal I/R, and that's why we precise effect

Conclusion

In conclusion, diabetes overstated renal damage induced by renal I/R via oxidative stress and inflammatory process in STZ-NAD-induced diabetes in rats. Also, the sitagliptin treatment attenuated renal injury induced by renal I/R in diabetic rats. This is the first study in which sitagliptin was used to prevent renal damage induced by renal I/R in diabetes, the prevention being shown to achieve via NO generation and neutrophil sequestration in the renal tissue.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Acknowledgments

We thank Dr. R. Balaraman (Head, Department of Pharmacology, M. S. University of Baroda) and Mr. Chintan Gandhi for their advice regarding ischemic injury in rat, and B. T. Savani Kidney Foundation for secretarial support in this work. The part of this study has been presented as poster in 61st Indian Pharmaceutical Congress Association (December – 2009).

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