Oxytocin alleviates cisplatin-induced renal damage in rats

Document Type: Original Article

Authors

1 Gaziosmanpasa University Faculty of Medicine, Department of Physiology, Tokat Turkey

2 Izmir Dr Behcet Uz Pediatric Medicine and Surgery Training and Research Hospital, Pediatric Endocrinology Clinic, Izmir, Turkey

3 Ege University School of Medicine, Department of Histology and Embryology, Izmir, Turkey

4 Ege University School of Medicine, Department of Gynecology and Obstetrics, Izmir, Turkey

5 Gaziosmanpasa University Faculty of Medicine, Department of Neurology, Tokat, Turkey

6 Ege University Faculty of Medicine, Department of Physiology, Izmir, Turkey

Abstract

Objective(s):The purpose of the present study was to investigate the protective effect of oxytocin on cisplatin (CP)-induced renal damage in rats.
Materials and Methods: Fourteen adult Sprague Dawley rats, weighing 200 to 210, were administered by cisplatin (CP, 2 mg/kg/day) twice a week for five weeks. Then, they were randomly divided into two groups and treated with either saline (1 ml/kg/day) or OT                       (200 µg/kg/day) for five weeks. Seven rats served as control group. At the end of the treatment period, animals were sacrificed and their kidneys were assessed histologically. In addition,            C-reactive protein (CRP), TGF-β and Akt expression were evaluated immunohistochemically.
Results:Both tubules and glomeruli were found to be severely damaged with marked medullary tubulo-interstitial inflammation due to chronic cisplatin exposure, particularly in the saline-treated group (Group 1) compared to control group. Oxytocin treatment spared renal tissue significantly by suppressing CRP and TGF-β, and enhancing Akt expression.
Conclusion: We conclude that renal damage due to cisplatin toxicity was prevented to a great extent by the anti-inflammatory effect of oxytocin.   

Keywords


1. Ries F, Klastersky J. Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity. Am J Kidney Dis 1986; 8:368-379.

2. Wang D, Lippard SJ. Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 2005; 4:307-320.

3. Atessahin A, Yilmaz S, Karahan I, Ceribasi AO, Karaoglu A. Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats. Toxicology 2005; 212:116-123.

4. Tikoo K, Bhatt DK, Gaikwad AB, Sharma V, Kabra DG. Differential effects of tannic acid on cisplatin induced nephrotoxicity in rats. FEBS Lett 2007; 581:2027-2035.

5. Jordan P, Carma-Fonseca M. Molecular mechanism involved in cisplatin cytotoxicity. Cell Mol Life Sci 2000; 57:1229-1235.

6. Sadzaku Y, Shoji T, Takino Y. Mechanism of the increase in lipid peroxide induced by cisplatin in the kidney rats. Toxicol Lett 1992; 62:293-300.

7. Chirino YI, Pedraza-Chaverri J. Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Exp Toxicol Pathol 2009; 61:223-242.

8. Davis CA, Nick HS, Agarwal A. Manganese superoxide dismutase attenuates Cisplatin-induced renal injury: importance of superoxide. J Am Soc Nephrol 2001; 12:2683-2690.

9. Pabla N, Dong Z. Cispaltin nephrotoxicity: mechanism and renoprotective strategies. Kidney Int 2008; 73:994-1007.

10. Ramesh G, Reeves WB. Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-alpha. Kidney Int 2004; 65:490-499.

11.Yamate J, Sato K, Ide M, Nakanishi M, Kuwamura M, Sakuma S, et al. Participation of different macrophage populations and myofibroblastic cells in chronically developed renal interstitial fibrosis after cisplatin-induced renal injury in rats. Vet Pathol 2002; 39:322-333.

12. Yamate J, Machida Y, Ide M, Kuwamura M, Sawamoto O, La Marre J. Effects of lipopolysaccharide on the appearance of macrophage populations and fibrogenesis in cisplatin-induced rat renal injury. Exp Toxicol Pathol 2004; 56:13-24.

13. Olson BR, Hoffman GE, Sved AF, Stricker EM, Verbalis JG. Cholecystokinin induces c-fos expression in hypothalamic oxytocinergic neurons projecting to the dorsal vagal complex. Brain Res 1992; 569:238-248.

14. Yazawa H, Hirasawa A, Horie K, Saita Y, Iida E, Honda K, et al. Oxytocin receptors expressed and coupled to Ca2+ signalling in a human vascular smooth muscle cell line. Br J Pharmacol 1996; 117:799-804.

15. Jankowski M, Wang D, Hajjar F, Mukaddam-Daher S, McCann SM, Gutkowska J. Oxytocin and its receptors are synthesized in the rat vasculature. Proc Natl Acad Sci U S A 2000; 97:6207-6211.

16. Gutkowska J, Jankowski M. Oxytocin: old hormone, new drug. Pharmaceuticals 2009; 2:168-183.

17. Iseri SO, Sener G, Saglam B, Gedik N, Ercan F, Yegen BC. Oxytocin protects 376 against sepsis-induced multiple organ damage: role of neutrophils. J Surg Res 2005; 126:73-81.

18. Rashed LA, Hashem RM, Soliman HM. Oxytocin inhibits NADPH oxidase and P38 MAPK in cisplatin-induced nephrotoxicity. Biomed Pharmacother 2011; 65:474-480.

19. Erbas O, Ergenoglu AM, Akdemir A, Yeniel AO, Taskiran D. Comparison of melatonin and oxytocin in the prevention of critical illness polyneuropathy in rats with experimentally induced sepsis. J Surg Res 2012; 11:043.

20. Erbas O, Oltulu F, Taskiran D. Amelioration of rotenone-induced dopaminergic cell death in the striatum by oxytocin treatment. Peptides 2012; 38: 312-317.

21. Erdogan H, Fadillioğlu E, Kotuk M, Iraz M, Tasdemir S, Oztas Y, et al. Effects of Ginkgo biloba on plasma oxidant injury induced by bleomycin in rats. Toxicol Ind Health 2006; 22:47-52.

22. Ashrafi F, Nematbakhsh M, Safari T, Talebi A, Nasri H, Khazaei M, et al. A combination of vitamin C and losartan for cisplatin-induced nephrotoxicity in rats. Iran J Kidney Dis 2012; 6:361-365.

23. Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review. Am J Med Sci 2007; 334:115–124.

24. Lan HY. Tubular epithelial-myofibroblast transdifferentiation mechanism in proximal tubule cell. Curr Opin Nephrol Hypertens 2003; 12:25–29.

25. Yang J, Liu Y. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol 2001; 159:1465–1475.

26. Pick E, Moustakas A, Kurisaki A, Heldin CH, ten Dijke P. TGF-alpha 1 receptor/ALK-5 and Smad
proteins mediate epithelial to mesenchymal transdifferentiation in Nmu MG breast epithelial cells. J Cell Sci 1999; 112:4557–4568.

27. Bottinger EP, Bitzer M. TGF- alpha signaling in renal disease. J Am Soc Nephrol 2002; 13:2600–2610.

28. Oldfield MD, Bach LS, Forbes JM, Nikolic-Pateerson D, McRobert A, Thallas V, et al. Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). J Clin Invest 2001; 108:1853–1863.

29. Li JH, Wang W, Huang XR, Oldfield M, Schmidt AM, Cooper ME, et al. Advanced glycation end products induce tubular epithelial-myofibroblast transition through the RAGE-ERK1/2 MAP kinase signaling pathway. Am J Pathol 2004; 164:1389–1397.

30. Huang XR, Li JH, Chen YX, Johnson RJ, Lan HY. SMAD signaling, a novel pathway of angiotensin II-induced renal fibrosis. J Am Soc Nephrol 2003; 14:1535-1548.

31. Li JH, Zhu HJ, Huang XR. Smad7 inhibits fibrotic effect of TGF-_ on renal tubular epithelial cells by blocking Smad2 activation. J Am Soc Nephrol 2002; 13:1464–1472.

32. Bhowmick NA, Zent R, Ghiassi M, McDonnell M, Moses HL. Integrin -1 signaling is necessary for transforming growth factor-_ activation of p38 MAPK and epithelial plasticity. J Biol Chem 2001; 276: 46707–46713.

33. Stuveling EM, Hillege HL, Bakker SJ, Gans RO, De Jong PE, De Zeeuw D. C-reactive protein is associated with renal function abnormalities in a non-diabetic population. Kidney Int 2003; 63:654–661.

34. Jabs WJ, Logering BA, Gerke P, Kreft B, Wolber EM, Klinger MH, et al. The kidney as a second site of human C-reactive protein formation in vivo. Eur J Immunol 2003; 33:152–161.

35. Padilla ND, Bleeker WK, Lubbers Y, Rigter GM, Van Mierlo GJ, Daha MR, et al. Rat C-reactive protein activates the autologous complement system. Immunology 2003; 109:564-571.

36. Scheid MP, Woodgett JR. PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2001; 2:760-768.

37. Sanz AB, Santamaria B, Ruiz-Ortega M, Egido J, Ortiz A. Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol 2008; 19:1634-1642.

38. Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 2008; 9:231-241.