Research Article
BibTex RIS Cite

THE ROLE OF ERYTHROPOIETIN IN A RAT MODEL OF RENAL ISCHEMIA/ REPERFUSION INJURY

Year 2024, Volume: 5 Issue: 1, 16 - 21, 30.04.2024

Bahar Kartal Mehmet Fatih Bozkurt Ebru Alimoğulları Uygar Saçık

https://doi.org/10.52831/kjhs.1397920

Abstract

Objective: A powerful activator of erythroid progenitor cells, erythropoietin (EPO) is markedly elevated during hypoxia. A major cause of renal cell death is renal ischemia caused by artery blockage or organ transplantation, and reperfusion exacerbates the damage. The study aimed to investigate the effect of EPO treatment on renal injury following ischemia and reperfusion (I/R).
Method: Thirty rats assigned to five groups of six rats each as control, EPO, ischemia, ischemia/reperfusion (I/R) and I/R+EPO.The renal tissue samples were evaluated in terms of hematoxylin-eosin (H&E) staining for histopathological changes, immunoexpression of Beclin-1 for autophagy, and the TUNEL assay for apoptosis.
Results: The H&E staining showed the impairment in the tubular epithelium, glomerular and peritubular hemorrhage in the renal tissues of I/R group. Less histopathological changes were observed in I/R + EPO group. Renal tissue Beclin-1 immunoexpression and TUNEL positive cells were significantly increased in the I/R group compared with the others (p<0.05). Treatment with EPO decreased the number of the TUNEL positive cells and Beclin-1 expression.
Conclusion: The data showed that EPO treatment could be effective in reducing renal injury following renal I/R and alleviate histomorphological damage.

Keywords

Apoptosis Autophagy Erythropoietin Histolopathology Renal ischemia/reperfusion

References

  • Malek M, Nematbakhsh M. Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev. 2015;4(2):20.
  • Liano F, Pascual J. Madrid acute renal failure study group. Epide- miology of acute renal failure: A prospective, multicenter, commu- nity-based study. Kidney Int. 1996;50:811-818.
  • Sutton TA, Molitoris BA. Mechanisms of cellular injury in ischemic acute renal failure. Semin Nephrol.1998;18:490-497.
  • Sheridan AM, Bonventre JV. Cell biology and molecular mecha- nisms of injury in ischemic acute renal failure. Curr Opin Nephrol Hypertens. 2000;9:327-434.
  • Sirén AL, Ehrenreich H. Erythropoietin a novel concept for neuroprotection. Eur Arch Psychiatry Clin Neurosci. 2001;251:179-84.
  • Qiao X, Li R-S, Li H, et al. Intermedin protects against renal ischemia-reperfusion injury by inhibition of oxidative stress. Am J Physiol Renal Physiol. 2013;304(1):F112-F119.
  • Burger DE, Xiang F-L, Hammoud L, Jones DL, Feng Q. Erythropoietin protects the heart from ventricular arrhythmia during ischemia and reperfusion via neuronal nitric-oxide synthase. J Pharmacol Exp Ther. 2009;329(3):900-907.
  • Hochhauser E, Pappo O, Ribakovsky E, et al. Recombinant human erythropoietin attenuates hepatic injury induced by ischemia/reperfusion in an isolated mouse liver model. Apoptosis. 2008;13:77-86.
  • Gunnarson E, Song Y, Kowalewski JM, et al. Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection. Proc Natl Acad Sci USA. 2009;106(5):1602-1607.
  • Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147(4):728-741.
  • Cursio R, Colosetti P, Gugenheim J. Autophagy and liver ischemia-reperfusion injury. BioMed Research International. 2015;2015.
  • Marino G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 2014;15(2):81-94.
  • Chen Q, Kang J, Fu C. The independence of and associations among apoptosis, autophagy, and necrosis. Signal transduct target ther. 2018;3(1):18.
  • Liu Y, Levine B. Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ. 2015;22(3):367-376.
  • Liu L, Liu C, Hou L, et al. Protection against ischemia/reperfusion‑induced renal injury by co‑treatment with erythropoietin and sodium selenite. Mol Med Rep. 2015;12(6):7933-7940.
  • Korkmaz A, Kolonkaya D. Inhibiting inducible nitric oxide synthase with rutin reduces renal ischemia/reperfusion injury. Can J Surg. 2013;56(1).
  • Foiatto JC, Czeczko NG, Wietzikoski EGG, et al. Influence of chlorpromazine on renal histology of rats submitted to ischemia and reperfusion injury. Acta Cir Bras. 2016;31(11):759.
  • Cayli S, Erdemir F, Ocaklı S, et al. Interaction between Smad1 and p97/VCP in rat testis and epididymis during the postnatal development. Reprod Sci. 2012;19(2):190-201.
  • Gencer M, Karaca T, Güngör AN, et al. The protective effect of quercetin on IMA levels and apoptosis in experimental ovarian ischemia-reperfusion injury. Eur J Obstet Gynecol Reprod Biol. 2014;177:135-140.
  • Medeiros PJd, Villarim Neto A, Lima FP, Azevedo ÍM, Leão LRdS, Medeiros AC. Effect of sildenafil in renal ischemia/reperfusion injury in rats. Acta Cir Bras. 2010;25:490-495.
  • Remzi M, Javadli E, Özsoy M. Management of small renal masses: a review. World J Urol. 2010;28:275-281.
  • Choi DE, Jeong JY, Lim BJ, Lee KW, Shin Y-T, Na K-R. Pretreatment with darbepoetin attenuates renal injury in a rat model of cisplatin-induced nephrotoxicity. Korean J Intern Med. 2009;24(3):238.
  • Furuichi K, Kaneko S, Wada T. Chemokine/chemokine receptor-mediated inflammation regulates pathologic changes from acute kidney injury to chronic kidney disease. Clin Exp Nephrol. 2009;13:9-14.
  • Zhang J, Zhao D, Na N, et al. Renoprotective effect of erythropoietin via modulation of the STAT6/MAPK/NF-κB pathway in ischemia/reperfusion injury after renal transplantation. Int J Mol Med. 2018;41(1):25-32.
  • Erbayraktar S, de Lanerolle N, de Lotbinière A, et al. Carbamylated erythropoietin reduces radiosurgically-induced brain injury. Mol Med. 2006;12(4-6):74-80.
  • Siren AL, Ehrenreich H. Erythropoietin-a novel concept for neuroprotection. Eur Arch Psychiatry Clin Neurosci. 2001;25:179-184.
  • Celik M, Gökmen N, Erbayraktar S, Akhisaroglu M, Konakc S, Ulukus C, et al. Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci USA. 2002;99(4):2258-2263.
  • Erbayraktar S, Grasso G, Sfacteria A, et al. Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci USA. 2003;100(11):6741-6746.
  • Guneli E, Cavdar Z, Islekel H, et al.Erythropoietin protects the intestine against ischemia/reperfusion injury in rats. Mol Med. 2007;13(9-10):509-5117.
  • Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239-257.
  • Banaei S, Ahmadiasl N, Alihemmati A. Combination Anti-apoptotic effect of erythropoietin and melatonin on ischemia reperfusion-induced renal injury in rats. Acta Med Iran. 2016;54(10):624-630.
  • Kwak J, Kim JH, Jang HN, et al. Erythropoietin ameliorates ischemia/reperfusion-induced acute kidney injury via inflammasome suppression in mice. Int J Mol Sci. 2020;21(10):3453.
  • Lieberthal W, Koh JS, Levine JS. Necrosis and apoptosis in acute renal failure. Semin Nephrol. 1998;18:505-518.
  • Przyklenk K, Dong Y, Undyala VV, Whittaker P. Autophagy as a therapeutic target for ischaemia/reperfusion injury? Concepts, controversies, and challenges. Cardiovasc Res. 2012;94:197-205.
  • Cao QH, Liu F, Yang ZL, Fu XH, Yang ZH, Liu Q, et al. Prognostic value of autophagy related proteins ULK1, Beclin 1, ATG3, ATG5, ATG7, ATG9, ATG10, ATG12, LC3B and p62/SQSTM1 in gastric cancer. Am J Transl Res. 2016;8(9):3831.
  • Bendix I, Schulze C, Haefen VC, et al. Erythropoietin modulates autophagy signaling in the developing rat brain in an in vivo model of oxygen-toxicity. Int J Mol Sci. 2012;13:12939-12951.
  • Lee JA. Neuronal autophagy: A housekeeper or a fighter in neuronal cell survival? Exp Neurobiol. 2012;21:1-8.
  • Zhang YL, Zhang J, Cui LY, Yang S. Autophagy activation attenuates renal ischemia-reperfusion injury in rats. Exp Biol Med. 2015;240:1590-1598.
  • Moore EM, Nichol AD, Bernard SA, Bellomo R. Therapeutic hypothermia: benefits, mechanisms and potential clinical applications in neurological, cardiac and kidney injury. Injury. 2011;42:843-854.
  • Huang L, Liu Z, Wang L. Effects of ischemic post-conditioning on the expressions of LC3-II and Beclin-1 in the hippocampus of rats after cerebral ischemia and reperfusion. Open Life Sci. 2019;14:179-190 .
  • Meyer G, Czompa A, Reboul C, et al. The cellular autophagy markers Beclin-1 and LC3B-II are increased during reperfusion in fibrillated mouse hearts. Curr Pharm Des. 2013;19(39):6912-6918.
  • Cesen MH, Pegan K, Spes A, Turk B. Lysosomal pathways to cell death and their therapeutic applications. Exp Cell Res. 2012;318:1245-51.
  • Lee JS, Kim YJ, Kim CL, Lee GM. Differential induction of autophagy in caspase-3/7 down-regulating and Bcl-2 overexpressing recombinant CHO cells subjected to sodium butyrate treatment. J Biotechnol. 2012;161:34-41.
  • Xiao R, Teng M, Zhang Q, Shi XH, Huang YS. Myocardial autophagy after severe burn in rats. PLoS One. 2012;7:e39488.

Deneysel İskemi/Reperfüzyon Sıçan Modelinde Eritropoietinin Böbrek Hasarindaki Rolü

Year 2024, Volume: 5 Issue: 1, 16 - 21, 30.04.2024

Bahar Kartal Mehmet Fatih Bozkurt Ebru Alimoğulları Uygar Saçık

https://doi.org/10.52831/kjhs.1397920

Abstract

Amaç: Eritroid progenitör hücrelerinin güçlü bir aktivatörü olan eritropoietin (EPO), hipoksi sırasında belirgin şekilde yükselmektedir. Arteriyer blokaj veya organ bağışının neden olabileceği renal iskemi böbrek dokusundaki hücre ölümünün başlıca sebebi olmakla birlikte reperfüzyon oluşan bu hasarı arttırmaktadır.Bu çalışmada eritropoietin uygulanmasının iskemi/reperfüzyon (I/R) sonrasında böbreklerde oluşan hasar üzerindeki etkisini araştırmayı amaçladık.
Gereç ve yöntemler: Çalışmamızda 30 adet rat kullanıldı. Ratlar her grupta 6 adet olacak şekilde kontrol, EPO, iskemi, iskemi/reperfüzyon (I/R) ve I/R+EPO olmak üzere beş gruba ayrıldı. Böbrek doku örnekleri histopatolojik incelemeler için hematoksilin-eozin (H&E) ile boyandı, otofajiyi tespit edebilmek için Beclin-1 proteininin immünoekspresyonu ve apoptoz için TUNEL yöntemi kullanılarak değerlendirildi.
Bulgular: Histopatolojik incelemeler sonucunda iskemi reperfüzyon grubuna ait böbrek dokusunda böbrek tübüllerinin epitelinde bozulma, glomerüler ve peritübüler kanama olduğu tespit edildi. Otofajik bir belirteç olan Beclin-1 immünekspresyonu ve TUNEL pozitif apoptotik hücrelerin I/R grubuna ait örneklerde diğer gruplara kıyasla anlamlı olarak arttığı (p < 0.05) saptandı. Bunlara ek olarak, eritropoietin verilen grupta Beclin-1 ekspresyonunda ve TUNEL pozitif hücrelerin sayısında azalma gözlendi.
Sonuç: Bu çalışma ile elde ettiğimiz veriler doğrultusunda eritropoietin tedavisinin renal iskemi/reperfüzyon sonrası böbrek hasarını azaltmada ve histomorfolojik hasarı iyileştirmede etkili olabileceğini düşünmekteyiz.

Keywords

Apoptoz Eritropoietin Histolopatoloji Otofaji Renal iskemi/reperfüzyon

References

  • Malek M, Nematbakhsh M. Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev. 2015;4(2):20.
  • Liano F, Pascual J. Madrid acute renal failure study group. Epide- miology of acute renal failure: A prospective, multicenter, commu- nity-based study. Kidney Int. 1996;50:811-818.
  • Sutton TA, Molitoris BA. Mechanisms of cellular injury in ischemic acute renal failure. Semin Nephrol.1998;18:490-497.
  • Sheridan AM, Bonventre JV. Cell biology and molecular mecha- nisms of injury in ischemic acute renal failure. Curr Opin Nephrol Hypertens. 2000;9:327-434.
  • Sirén AL, Ehrenreich H. Erythropoietin a novel concept for neuroprotection. Eur Arch Psychiatry Clin Neurosci. 2001;251:179-84.
  • Qiao X, Li R-S, Li H, et al. Intermedin protects against renal ischemia-reperfusion injury by inhibition of oxidative stress. Am J Physiol Renal Physiol. 2013;304(1):F112-F119.
  • Burger DE, Xiang F-L, Hammoud L, Jones DL, Feng Q. Erythropoietin protects the heart from ventricular arrhythmia during ischemia and reperfusion via neuronal nitric-oxide synthase. J Pharmacol Exp Ther. 2009;329(3):900-907.
  • Hochhauser E, Pappo O, Ribakovsky E, et al. Recombinant human erythropoietin attenuates hepatic injury induced by ischemia/reperfusion in an isolated mouse liver model. Apoptosis. 2008;13:77-86.
  • Gunnarson E, Song Y, Kowalewski JM, et al. Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection. Proc Natl Acad Sci USA. 2009;106(5):1602-1607.
  • Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147(4):728-741.
  • Cursio R, Colosetti P, Gugenheim J. Autophagy and liver ischemia-reperfusion injury. BioMed Research International. 2015;2015.
  • Marino G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 2014;15(2):81-94.
  • Chen Q, Kang J, Fu C. The independence of and associations among apoptosis, autophagy, and necrosis. Signal transduct target ther. 2018;3(1):18.
  • Liu Y, Levine B. Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ. 2015;22(3):367-376.
  • Liu L, Liu C, Hou L, et al. Protection against ischemia/reperfusion‑induced renal injury by co‑treatment with erythropoietin and sodium selenite. Mol Med Rep. 2015;12(6):7933-7940.
  • Korkmaz A, Kolonkaya D. Inhibiting inducible nitric oxide synthase with rutin reduces renal ischemia/reperfusion injury. Can J Surg. 2013;56(1).
  • Foiatto JC, Czeczko NG, Wietzikoski EGG, et al. Influence of chlorpromazine on renal histology of rats submitted to ischemia and reperfusion injury. Acta Cir Bras. 2016;31(11):759.
  • Cayli S, Erdemir F, Ocaklı S, et al. Interaction between Smad1 and p97/VCP in rat testis and epididymis during the postnatal development. Reprod Sci. 2012;19(2):190-201.
  • Gencer M, Karaca T, Güngör AN, et al. The protective effect of quercetin on IMA levels and apoptosis in experimental ovarian ischemia-reperfusion injury. Eur J Obstet Gynecol Reprod Biol. 2014;177:135-140.
  • Medeiros PJd, Villarim Neto A, Lima FP, Azevedo ÍM, Leão LRdS, Medeiros AC. Effect of sildenafil in renal ischemia/reperfusion injury in rats. Acta Cir Bras. 2010;25:490-495.
  • Remzi M, Javadli E, Özsoy M. Management of small renal masses: a review. World J Urol. 2010;28:275-281.
  • Choi DE, Jeong JY, Lim BJ, Lee KW, Shin Y-T, Na K-R. Pretreatment with darbepoetin attenuates renal injury in a rat model of cisplatin-induced nephrotoxicity. Korean J Intern Med. 2009;24(3):238.
  • Furuichi K, Kaneko S, Wada T. Chemokine/chemokine receptor-mediated inflammation regulates pathologic changes from acute kidney injury to chronic kidney disease. Clin Exp Nephrol. 2009;13:9-14.
  • Zhang J, Zhao D, Na N, et al. Renoprotective effect of erythropoietin via modulation of the STAT6/MAPK/NF-κB pathway in ischemia/reperfusion injury after renal transplantation. Int J Mol Med. 2018;41(1):25-32.
  • Erbayraktar S, de Lanerolle N, de Lotbinière A, et al. Carbamylated erythropoietin reduces radiosurgically-induced brain injury. Mol Med. 2006;12(4-6):74-80.
  • Siren AL, Ehrenreich H. Erythropoietin-a novel concept for neuroprotection. Eur Arch Psychiatry Clin Neurosci. 2001;25:179-184.
  • Celik M, Gökmen N, Erbayraktar S, Akhisaroglu M, Konakc S, Ulukus C, et al. Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci USA. 2002;99(4):2258-2263.
  • Erbayraktar S, Grasso G, Sfacteria A, et al. Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci USA. 2003;100(11):6741-6746.
  • Guneli E, Cavdar Z, Islekel H, et al.Erythropoietin protects the intestine against ischemia/reperfusion injury in rats. Mol Med. 2007;13(9-10):509-5117.
  • Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239-257.
  • Banaei S, Ahmadiasl N, Alihemmati A. Combination Anti-apoptotic effect of erythropoietin and melatonin on ischemia reperfusion-induced renal injury in rats. Acta Med Iran. 2016;54(10):624-630.
  • Kwak J, Kim JH, Jang HN, et al. Erythropoietin ameliorates ischemia/reperfusion-induced acute kidney injury via inflammasome suppression in mice. Int J Mol Sci. 2020;21(10):3453.
  • Lieberthal W, Koh JS, Levine JS. Necrosis and apoptosis in acute renal failure. Semin Nephrol. 1998;18:505-518.
  • Przyklenk K, Dong Y, Undyala VV, Whittaker P. Autophagy as a therapeutic target for ischaemia/reperfusion injury? Concepts, controversies, and challenges. Cardiovasc Res. 2012;94:197-205.
  • Cao QH, Liu F, Yang ZL, Fu XH, Yang ZH, Liu Q, et al. Prognostic value of autophagy related proteins ULK1, Beclin 1, ATG3, ATG5, ATG7, ATG9, ATG10, ATG12, LC3B and p62/SQSTM1 in gastric cancer. Am J Transl Res. 2016;8(9):3831.
  • Bendix I, Schulze C, Haefen VC, et al. Erythropoietin modulates autophagy signaling in the developing rat brain in an in vivo model of oxygen-toxicity. Int J Mol Sci. 2012;13:12939-12951.
  • Lee JA. Neuronal autophagy: A housekeeper or a fighter in neuronal cell survival? Exp Neurobiol. 2012;21:1-8.
  • Zhang YL, Zhang J, Cui LY, Yang S. Autophagy activation attenuates renal ischemia-reperfusion injury in rats. Exp Biol Med. 2015;240:1590-1598.
  • Moore EM, Nichol AD, Bernard SA, Bellomo R. Therapeutic hypothermia: benefits, mechanisms and potential clinical applications in neurological, cardiac and kidney injury. Injury. 2011;42:843-854.
  • Huang L, Liu Z, Wang L. Effects of ischemic post-conditioning on the expressions of LC3-II and Beclin-1 in the hippocampus of rats after cerebral ischemia and reperfusion. Open Life Sci. 2019;14:179-190 .
  • Meyer G, Czompa A, Reboul C, et al. The cellular autophagy markers Beclin-1 and LC3B-II are increased during reperfusion in fibrillated mouse hearts. Curr Pharm Des. 2013;19(39):6912-6918.
  • Cesen MH, Pegan K, Spes A, Turk B. Lysosomal pathways to cell death and their therapeutic applications. Exp Cell Res. 2012;318:1245-51.
  • Lee JS, Kim YJ, Kim CL, Lee GM. Differential induction of autophagy in caspase-3/7 down-regulating and Bcl-2 overexpressing recombinant CHO cells subjected to sodium butyrate treatment. J Biotechnol. 2012;161:34-41.
  • Xiao R, Teng M, Zhang Q, Shi XH, Huang YS. Myocardial autophagy after severe burn in rats. PLoS One. 2012;7:e39488.
There are 44 citations in total.

Details

Primary Language English
Subjects Nefroloji
Journal Section Research Articles
Authors

Bahar Kartal 0000-0001-9558-4122

Mehmet Fatih Bozkurt 0000-0002-1669-0988

Ebru Alimoğulları 0000-0002-9557-3631

Uygar Saçık 0000-0002-3154-8779

Publication Date April 30, 2024
Submission Date November 29, 2023
Acceptance Date February 13, 2024
Published in Issue Year 2024 Volume: 5 Issue: 1

Cite

Vancouver Kartal B, Bozkurt MF, Alimoğulları E, Saçık U. THE ROLE OF ERYTHROPOIETIN IN A RAT MODEL OF RENAL ISCHEMIA/ REPERFUSION INJURY. Karya J Health Sci. 2024;5(1):16-21.
 Download Cover Image


This material is licensed by Creative Commons Attribution-NonCommercial-No Derivative 4.0 International License.