Combination Anti-Apoptotic Effect of Erythropoietin and Melatonin on Ischemia Reperfusion-Induced Renal Injury in Rats
AbstractRenal ischemia-reperfusion (IR) contributes to the development of acute renal failure (ARF). Oxygen free radicals are considered to be principal components involved in the pathophysiological tissue alterations observed during renal IR. The purpose of this study was to investigate the combination effect of melatonin (MEL) and erythropoietin (EPO), which are a potent antioxidant and anti-apoptotic agents, in IR-induced renal injury in rats. Wistar Albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h reperfusion. MEL (10 mg/kg, i.p) and EPO (5000 U/kg, i.p) were administered prior to ischemia. After 24 h reperfusion, following decapitation, blood samples were collected for the determination of superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels. Also, renal samples were taken for histological evaluation and apoptosis assay. Ischemia-reperfusion increased SOD, GPx, MDA levels, and TUNEL positive cells. Histopathological findings of the IR group confirmed that there was renal impairment in the tubular epithelium. Treatment with EPO and MEL decreased SOD, GPx, and MDA levels, histopathological changes, and TUNEL positive cells. These results indicated that the combination of MEL and EPO could not exert more nephroprotective and anti-apoptotic effects than MEL treatment in renal ischemia-reperfusion injury.
Ploeg RJ, van Bockel JH, Langendijk PT, Groenewegen M, van der Woude FJ, Persijn GG, et al. Effect of preservation solution on results of cadaveric kidney transplantation. The European Multicentre Study Group. Lancet 1992;340:129-37.
Edelstein CL, Ling H, Schrier RW. The nature of renal cell injury. Kidney Int 1997;51:1341-51.
Lemasters JJ, Thurman RG. Reperfusion injury after liver preservation for transplantation. Annu Rev Pharmacol Toxicol 1997;37:327-38.
Kacmaz A, Polat A, User Y, Tilki M, Ozkan S, Sener G.Octreotide improves reperfusion-induced oxidative injury in acute abdominal hypertension in rats. J Gastrointest Surg 2004;8:113-9.
Cau J, Favreau F, Zhang K, Febrer G, de la Motte GR, Ricco JB, et al. FR167653 improves renal recovery and decreases inflammation and fibrosis after renal ischemia- reperfusion injury. J Vasc Surg 2009;49:728-40.
Korkmaz A, Kolankaya D. The protective effects of ascorbic acid against renal ischemia-reperfusion injury in male rats. Ren Fail 2009;31:36-43.
Benjamin B, Ebert L, Bunn HF. Regulation of erythropoietin gene. Blood 1999;94:1864-77.
Westenfelder C, Biddle DL, Baranowski RL. Human, rat, and mouse kidney cells express functional erythropoietin receptors. Kidney Int 1999;55:808-20.
Calo LA, Bertipaglia L, Pagnin E. Antioxidants, carnitine and erythropoietin. G Ital Nefrol 2006;34:47-50.
Plotnikov EY, Chupyrkina AA, Jankauskas SS, Pevzner IB, Silachev DN, Skulachev VP, et al. Mechanisms of nephroprotectiv effect of mitochondria-targeted antioxidants under rhabdomyolysis and ischemia/reperfusion.iochim Biophys Acta 2011;1812:77-86.
Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, et al. Melatonin: a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro. Ann NY Acad Sci 1994;738:419-20.
Mayo JC, Sainz RM, Tan DX, Hardeland R, Leon J, Rodriguez C, et al. Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5- methoxykynuramine (AFMK) and N1-acetyl-5- methoxykynuramine(AMK), in macrophages. J Neuroimmunol 2005;165(1-2):139-49.
Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 2004;36:1-9.
Reiter RJ, Guerrero JM, Garcia JJ, Acuna-Castroviejo D.Reactive oxygen intermediates, molecular damage, and aging: relation to melatonin. Ann NY Acad Sci1998;854:410-24.
Kaya H, Sezik M, Ozkaya O, Dittrich R, Siebzehnrubl E, Wildt L. Lipid peroxidation at various estradiol concentrations in human circulation during ovarian stimulation with exogenous gonadotropins. Horm Metab Res 2004;36:693-5.
Paglia DE and Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967;70:158-69.
Sšzmen Ey, Sšzmen B, Delen Y and Onat T.Catalase/Superoxide Dismutase (SOD) and Catalase/Paraoxanase (PON) ratio may implicate poor glycemic control. Arch Med Res 2001;32:283-7.
Kiris I, Kapan S, Kilbas A, Yilmaz N, Altuntaş I, Karahan N, et al. The protective effect of erythropoietin on renal injury induced by abdominal aortic-ischemia- reperfusion in rats. J Surg Res 2008;149:206-13.
Gobe G, Zhang XJ, Willgoss DA, Schoch E, Hogg NA, Endre ZH. Relationship between expression of Bvl-2 genes and growth factors in ischemic acute renal failure in the rat. J Am Soc Nephrol 2000;11:454-67.
Carden DL, Granger DN. Pathophysiology of ischemia reperfusion injury. J Pathol 2000;190:255-66.
McCord JM. The evaluation of free radicals and oxidative stress. Am J Med 2000;108:652-9.
Ates E, Yalcin AU, Yılmaz S, Koken T, Tokyol C.Protective effect of erythropoietin on renal ischemia and reperfusion injury. ANZ J Surg 2005;75:1100-5.
Reiter RJ, OH C-S, Fujimori O. Melatonin: its intracellular and genomic actions. Trends Endocrinol Metab 1996;7:22-7.
Schoenberg MH, Beger HG. Reperfusion injury after intestinal ischemia. Crit Med Care 1993;21:1376-86.
Mun KC, Lee HG, Lee TH, Kim YH, Kwak CS, Kim SP,et al. Effect of modified polyhemoglobin on the ischemia/reperfusion injury in kidney. Transplant Proc 2003;35:99-100.
Kiris I, Okutan H, Savas C, Yönden Z, Delibaş N.Deneysel aortic iskemi-reperfuzyon modelinde renal hasara gadolinium klorurun etkisi. Turkish J Vasc Surg 2005;14:13-8.
Chen CF, Hsueh CW, Tang TS, Wang D, Shen CY, Pei JS. Reperfusion liver injury induced superoxide dismutase and catalase expressions and the protective effects of N-acetyl cysteine. Transplant Proc2007;39:858-60.
Gulmen S, Kiris I, Narin C, Ceylan BG, Mermi B, Sutcu R, et al. Tezosentan reduces the renal injury induced by abdominal aortic ischemia-reperfusion in rats. J Surg Res 2009;157:e7-13.
Sharples EJ, Patel N, Brown P, Stewart K, Mota-Philipe H, Sheaff M, et al. Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia- reperfusion. J Am Soc Nephrol 2004;15:2115-24.
Sener G, Sehirli AO, Keyer-Uysal M, Arbak S, Ersoy Y, Yegen BC. The protective effect of melatonin on renal ischemia-reperfusion injury in the rat. J. Pineal Res 2002;32:120-6.
Lieberthal W, Koh JS, Levine JS. Necrosis and apoptosis in acute renal failure. Semin Nephrol 1998;18:505-18.
Spandou E, Tsouchnikas I, Karkavelas G, Dounousi E, Simeonidou C, Guiba-Tziampiri O, et al. Erythropoietin attenuates renal injury in experimental acute renal failure ischaemic/reperfusion model. Nephrol Dial Transplant 2006;21:330-6.
Taghizadieh M, Hajipour B, Ahmadi Asl N, Khodadadi A, Somi MH. Co-administration of Melatonin and Dexamethasone Attenuates Lung Tissue Injury after Liver Ischemia/Reperfusion. Life Sci J 2013;10:314-20.
Ahmadiasl N, Banaei S, Alihemmati A. Combination antioxidant effect of erythropoietin and melatonin on renal ischemia-reperfusion injury in rats. Iran J Basic Med Sci 2013; 16:1209-16.
Ahmadiasl N, Banaei S, Alihemmati A, Baradaran B, Azimian E. The anti-inflammatory effect of rythropoietin and melatonin on renal ischemia reperfusion injury in male rats. Adv Pharm Bull 2014;4:49-54.