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The Effect of Erythropoietin on Methotrexate-Induced Renal Damage in Rats: Biochemical and Histopathological Studies

Year 2015, Volume: 40 Issue: 1, 98 - 106, 09.09.2015
https://doi.org/10.17826/cutf.23047

Abstract

Purpose: Methotrexate (MTX), a folic acid antagonist, is widely used as a cytotoxic chemotherapeutic agent for several malignancies and various inflammatory diseases. However, the efficacy of this agent often is limited by severe side effects and toxic conditions. In our study, it was aimed to investigate the effect of erythropoietin (EPO) which is a potent antioxidant substance in oxidative damage induced-MTX. Material and Methods: Twenty-four female Sprague-Dawley sıçans were equally divided into three groups: Sham animals were administered subcutaneous injections of 0.2 mL of 0.9% NaCl, group MTX were administered subcutaneous injections of methotrexate (5 mg/kg), and MTX+EPO-treated animals were administered subcutaneous injections of methotrexate (5 mg/kg) and EPO (2000 IU/kg) once daily for 4 consecutive days. At the fifth day, the Araştırma Makalesi / Research Article 98 Cilt/Volume 40 Yıl/Year 2015 Metotreksat -Eritropoetinin animals were sacrified, and kidneys were excised. Catalase (CAT), superoxide dismutase (SOD) and malondialdehyde (MDA) in kidney tissue homogenates were measured as spectrophotometric. Tissues were evaluated as histopathologic with ligh microscope. Results: MDA levels in the Sham and MTX+EPO groups were significantly lower than those in the MTX group of both tissues (p<0.05). CAT and SOD activities in the Sham and MTX+EPO groups were significantly higher than those in the MTX group (p<0.05). Both tissues damage was significantly less in the MTX+EPO group than that in the MTX (p<0.05). EPO treatment reduced these histological damages. Conclusion: These data indicate that EPO may be useful therapeutic use in preventing kidney injury in patients receiving chemotherapeutic agents

References

  • Cetinkaya A, Bulbuloglu E, Kurutas EB, Kantarceken B. N-acetylcysteine ameliosıçanes methotrexate- induced oxidative liver damage in rats. Med Sci Monit. 2006;12:BR274-78.
  • Dutz JP, Ho VC. Immunosuppressive agents in dermatology. An update. Dermatol Clin. 1998;16:235- 51.
  • Flores F, Kerdel FA. Other novel immunosuppressants. Dermatol Clin. 2000;18:475- 83.
  • Madhyastha S, Somayaji SN, Rao MS, Nalini K, Bairy KL. Hippocampal brain amines in methotrexate induced learning and memory deficit. J Physiol Pharmacol. 2002;80:1076-84.
  • Jolivet J, Cowan KH, Curt GA, Clendeninn NJ, Chabner BA. The pharmacology and clinical use of methotrexate. N Engl J Med 1983;309:1094-104.
  • Sener G, Eksioglu-Demiralp E, Cetiner M, Ercan F, Yegen BC. Beta-glucan ameliosıçanes methotrexate- induced oxidative organ injury via its antioxidant and immunomodulatory effects. Eur J Pharmacol. 2006;542:170-8.
  • Jahovic N, Cevik H, Sehirli Ao, Yeğen BC, Sener G.
  • Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats. J Pineal Res. 2003;34:282-7
  • Kolli VK, Abraham P, Isaac B, Selvakumar D. Neutrophil infiltsıçanion and oxidative stress may play a critical role in methotrexate-induced renal damage. Chemotherapy. 2009;55:83-90.
  • Miyazono Y, Gao F, Horie T. Oxidative stress contributes to methotrexate-induced small intestinal toxicity in rats. Scand J Gastroenterol. 2004;39:1119- 27.
  • Uysal M. Serbest radikaller, lipit peroksitleri organizmada prooksidan-antioksidan dengeyi etkileyen koşullar. Klinik gelişim. 1998;1:336-41.
  • Serafini M, Del Rio D. Understanding the association between dietray antioxidants, redox status and disease: Is the Total Antioxidant Capacity the right tool?. Redox Rep. 2004;9:145-52.
  • Hermes-Lima M, Zenteno-Savin T. Animal response to drastic changes in oxygen availability and physiological oxidative stress. Comp Biochem Physiol C Toxicol pharmacol. 2002;133:537-56.
  • Halliwell B. Tell me about free radicals, doctor: a review. J R Soc Med. 1989;82:747-52.
  • Freeman BA, Crapo JD. Biology of disease: free radicals and tissue injury. Lab Invest. 1982;47:412- 26.
  • Koury ST, Bondurant MC, Koury MJ. Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood. 1988;71:524-27.
  • Krantz SB. Erythropoietin. Blood. 1991;77:419-34.
  • Wang FF, Kung SC, Goldwasser E. Some chemical properties of human erythropoietin. Endocrinology. 1985;116:2286-92.
  • Fisher JW: Erythropoietin, in Textbook of Nephrology (vol 3), edited by Massry SG, Glassock RJ, New York, Williams and Wilkins, 1989;1:175-180.
  • Baker JE. Erythropoietin mimics ischemic preconditioning. Vascul Pharmacol. 2005;42:233-41.
  • Ates E, Yalcın AU, Yılmaz S, Köken T, Tokyol C. Protective effect of erythropoietin on renal ischemia and reperfusion injury. ANZ J Surg. 2005;75:1100-5.
  • Beutler E. Red Cell Metabolism. New York, Grune and Stratton. 1975.
  • Fridovich I. Superoxide radical: an endogenous toxicant. Annu Rev Pharmacol Toxicol. 1983;23:239– 57.
  • Ohkawa H, Ohishi N, Tagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95:351–8.
  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:265.
  • Miketova P, Kaemingk K, Hockenberry M, Pasvogel A, Hutter J, Krull K, Moore IMOxidative changes in cerebral spinal fluid phosphatidylcholine during treatment for acute lymphoblastic leukemia. Biol Res Nurs. 2005;6:187-95.
  • Jahovic N, Sener G, Cevik H, Ersoy Y, Arbak S, Yegen BC. Amelioration of methotrexate-induced enteritis by melatonin in rats. Cell Biochem Funct. 2004;22:169-78.
  • Devrim E, Cetin R, Kiliçoglu B, Ergüder BI, Avci A, Durak I. Methotrexate causes oxidative stress in rat kidney tissues. Ren Fail. 2005;27:771-3.
  • Uz E, Oktem F, Yilmaz HR, Uzar E, Ozgüner F. The activities of purine-catabolizing enzymes and the level of nitric oxide in rat kidneys subjected to methotrexate: protective effect of caffeic acid phenethyl ester. Mol Cell Biochem 2005;277:165-70.
  • Babiak RM, Campello AP, Carnieri EG, Oliveira MB. Methotrexate: pentose cycle and oxidative stress. Cell Biochem Funct. 1998;16:283-93.
  • Joyeux-Faure M, Godin-Ribuot D, Ribuot C. Erythropoietin and myocardial protection: what's new? Fundam Clin Pharmacol. 2005;19:439-46.
  • Sepodes M et al. Recombinant human erythropoietin protects the liver from hepatic ischemia-reperfusion injury in the rat. Transpl Int. 2006;19:919-26.
  • Kumral A, Tugyan K, Gonenc S, Genc K, Genc S, Sonmez U, Yilmaz O, Duman N, Uysal N, Ozkan H. Protective effects of erythropoietin against ethanol- induced apoptotic neurodegeneration and oxidative stress in the developing C57BL/6 mouse brain. Brain Res Dev Brain Res. 2005;160:146-56.
  • Genc S, Koroğlu TF, Genc K. Erythropoietin as a novel neuroprotectant. Restor Neurol Neurosci. 2004;22:105-19.

Metotreksat ile İndüklenmiş Sıçanlarda Böbrek Hasarı Üzerine Eritropoetinin Etkisi: Biyokimyasal ve Histopatolojik Çalışma

Year 2015, Volume: 40 Issue: 1, 98 - 106, 09.09.2015
https://doi.org/10.17826/cutf.23047

Abstract

Amaç: Metotreksat (MTX) çeşitli inflamatuvar hastalıklarda ve bazı kanserler de çok yaygın olarak kullanılan sitotoksik bir ajan olup folik asit antagonistidir. Etkili bir ilaç olmasına rağmen, sıklıkla yan etki ve toksik etkileri nedeni ile kullanımı kısıtlanmaktadır. Çalışmamızda, güçlü bir antioksidan madde olan Eritropoetin (EPO)’in MTX’e bağlı olarak oluşan oksidatif hasara karşı etkisinin araştırılması amaçlandı. Materyal ve Metod: Yirmi dört adet dişi Sprague-Dawley sıçan üç gruba ayrıldı. Gruplar; % 0,9’luk NaCI’den 0,2 mL subkutan enjeksiyon uygulanan Sham grubu; subkutan MTX (5mg/kg) enjeksiyonu uygulanan grup ve subkutan MTX (5mg/kg) ile EPO (2000 IU/kg) enjeksiyonu uygulanan grup olarak belirlendi. İşlem günde bir kez olmak üzere 4 gün boyunca uygulandı. Beşinci günde sıçanlar öldürüldü, böbrek dokuları çıkarıldı. Böbrek dokularında katalaz (CAT), süperoksit dismutaz (SOD) ve malondialdehit (MDA) düzeyleri spektrofotometrik olarak ölçüldü. Dokuların histopatolojik incelemesi ışık mikroskopisinde yapıldı. Bulgular: Böbrek dokusunda MDA düzeyleri, Sham grubu ve MTX+EPO grubunda, MTX grubuna göre önemli ölçüde düşük bulundu (p<0,05). Buna karşın, Sham grubu ve MTX+EPO grubunda CAT ve SOD aktiviteleri anlamlı derecede yüksek bulundu (p<0,05). MTX+EPO grubunda hem karaciğer hem de böbrek doku hasarının MTX grubu ile kıyaslandığında önemli ölçüde azaldığı gözlendi (p<0,05). Histopatolojik olarak sadece metotreksat verilen grupta belirgin tübül hasarı ve enflamasyon varken EPO uygulanan gruplarda bu hasarlar azalmıştı. Sonuç: Bu veriler, EPO’ nun kemoterapötik ilaçlara bağlı oluşan böbrek hasarına karşı koruyucu olarak kullanılabileceğini ortaya koymaktadır

References

  • Cetinkaya A, Bulbuloglu E, Kurutas EB, Kantarceken B. N-acetylcysteine ameliosıçanes methotrexate- induced oxidative liver damage in rats. Med Sci Monit. 2006;12:BR274-78.
  • Dutz JP, Ho VC. Immunosuppressive agents in dermatology. An update. Dermatol Clin. 1998;16:235- 51.
  • Flores F, Kerdel FA. Other novel immunosuppressants. Dermatol Clin. 2000;18:475- 83.
  • Madhyastha S, Somayaji SN, Rao MS, Nalini K, Bairy KL. Hippocampal brain amines in methotrexate induced learning and memory deficit. J Physiol Pharmacol. 2002;80:1076-84.
  • Jolivet J, Cowan KH, Curt GA, Clendeninn NJ, Chabner BA. The pharmacology and clinical use of methotrexate. N Engl J Med 1983;309:1094-104.
  • Sener G, Eksioglu-Demiralp E, Cetiner M, Ercan F, Yegen BC. Beta-glucan ameliosıçanes methotrexate- induced oxidative organ injury via its antioxidant and immunomodulatory effects. Eur J Pharmacol. 2006;542:170-8.
  • Jahovic N, Cevik H, Sehirli Ao, Yeğen BC, Sener G.
  • Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats. J Pineal Res. 2003;34:282-7
  • Kolli VK, Abraham P, Isaac B, Selvakumar D. Neutrophil infiltsıçanion and oxidative stress may play a critical role in methotrexate-induced renal damage. Chemotherapy. 2009;55:83-90.
  • Miyazono Y, Gao F, Horie T. Oxidative stress contributes to methotrexate-induced small intestinal toxicity in rats. Scand J Gastroenterol. 2004;39:1119- 27.
  • Uysal M. Serbest radikaller, lipit peroksitleri organizmada prooksidan-antioksidan dengeyi etkileyen koşullar. Klinik gelişim. 1998;1:336-41.
  • Serafini M, Del Rio D. Understanding the association between dietray antioxidants, redox status and disease: Is the Total Antioxidant Capacity the right tool?. Redox Rep. 2004;9:145-52.
  • Hermes-Lima M, Zenteno-Savin T. Animal response to drastic changes in oxygen availability and physiological oxidative stress. Comp Biochem Physiol C Toxicol pharmacol. 2002;133:537-56.
  • Halliwell B. Tell me about free radicals, doctor: a review. J R Soc Med. 1989;82:747-52.
  • Freeman BA, Crapo JD. Biology of disease: free radicals and tissue injury. Lab Invest. 1982;47:412- 26.
  • Koury ST, Bondurant MC, Koury MJ. Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood. 1988;71:524-27.
  • Krantz SB. Erythropoietin. Blood. 1991;77:419-34.
  • Wang FF, Kung SC, Goldwasser E. Some chemical properties of human erythropoietin. Endocrinology. 1985;116:2286-92.
  • Fisher JW: Erythropoietin, in Textbook of Nephrology (vol 3), edited by Massry SG, Glassock RJ, New York, Williams and Wilkins, 1989;1:175-180.
  • Baker JE. Erythropoietin mimics ischemic preconditioning. Vascul Pharmacol. 2005;42:233-41.
  • Ates E, Yalcın AU, Yılmaz S, Köken T, Tokyol C. Protective effect of erythropoietin on renal ischemia and reperfusion injury. ANZ J Surg. 2005;75:1100-5.
  • Beutler E. Red Cell Metabolism. New York, Grune and Stratton. 1975.
  • Fridovich I. Superoxide radical: an endogenous toxicant. Annu Rev Pharmacol Toxicol. 1983;23:239– 57.
  • Ohkawa H, Ohishi N, Tagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95:351–8.
  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:265.
  • Miketova P, Kaemingk K, Hockenberry M, Pasvogel A, Hutter J, Krull K, Moore IMOxidative changes in cerebral spinal fluid phosphatidylcholine during treatment for acute lymphoblastic leukemia. Biol Res Nurs. 2005;6:187-95.
  • Jahovic N, Sener G, Cevik H, Ersoy Y, Arbak S, Yegen BC. Amelioration of methotrexate-induced enteritis by melatonin in rats. Cell Biochem Funct. 2004;22:169-78.
  • Devrim E, Cetin R, Kiliçoglu B, Ergüder BI, Avci A, Durak I. Methotrexate causes oxidative stress in rat kidney tissues. Ren Fail. 2005;27:771-3.
  • Uz E, Oktem F, Yilmaz HR, Uzar E, Ozgüner F. The activities of purine-catabolizing enzymes and the level of nitric oxide in rat kidneys subjected to methotrexate: protective effect of caffeic acid phenethyl ester. Mol Cell Biochem 2005;277:165-70.
  • Babiak RM, Campello AP, Carnieri EG, Oliveira MB. Methotrexate: pentose cycle and oxidative stress. Cell Biochem Funct. 1998;16:283-93.
  • Joyeux-Faure M, Godin-Ribuot D, Ribuot C. Erythropoietin and myocardial protection: what's new? Fundam Clin Pharmacol. 2005;19:439-46.
  • Sepodes M et al. Recombinant human erythropoietin protects the liver from hepatic ischemia-reperfusion injury in the rat. Transpl Int. 2006;19:919-26.
  • Kumral A, Tugyan K, Gonenc S, Genc K, Genc S, Sonmez U, Yilmaz O, Duman N, Uysal N, Ozkan H. Protective effects of erythropoietin against ethanol- induced apoptotic neurodegeneration and oxidative stress in the developing C57BL/6 mouse brain. Brain Res Dev Brain Res. 2005;160:146-56.
  • Genc S, Koroğlu TF, Genc K. Erythropoietin as a novel neuroprotectant. Restor Neurol Neurosci. 2004;22:105-19.
There are 34 citations in total.

Details

Primary Language English
Journal Section Research
Authors

Betül Kabakcı This is me

Ergül Kurutaş

Sevgi Bakariş This is me

Meltem Güngör This is me

Publication Date September 9, 2015
Published in Issue Year 2015 Volume: 40 Issue: 1

Cite

MLA Kabakcı, Betül et al. “The Effect of Erythropoietin on Methotrexate-Induced Renal Damage in Rats: Biochemical and Histopathological Studies”. Cukurova Medical Journal, vol. 40, no. 1, 2015, pp. 98-106, doi:10.17826/cutf.23047.