Effect of infliximab, a tumor necrosis factor-alpha inhibitor, on doxorubicin-induced nephrotoxicity in rats

  • Aly M. Abdelrahman
  • Yousuf M. Al Suleimani
  • Priyadarsini Manoj
  • Mohammed Ashique
  • Badreldin H. Ali
  • Nicole SchuppEmail author
Original Article


Treatment with the chemotherapeutic agent, doxorubicin (DOX), is limited by nephrotoxicity. We investigated the possible protective effect of infliximab, a tumor necrosis factor alpha (TNF-α) inhibitor on DOX-induced nephrotoxicity. Rats were treated with a single intraperitoneal (ip) injection of DOX (17.5 mg/kg) in the absence or presence of infliximab (5 mg/kg, i.p.). Plasma and urinary markers of kidney function, oxidative stress, and inflammation were measured. Kidney and heart tissue was evaluated histopathologically. DOX-induced nephrotoxicity was confirmed by increased plasma urea, creatinine, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and clusterin concentrations. In addition, DOX increased urinary albumin/creatinine ratio, N-acetyl-β-D-glucosaminidase (NAG) activity, kidney injury molecule (KIM-1) concentrations, and reduced creatinine clearance. DOX significantly reduced renal antioxidants and increased plasma inflammatory markers and adiponectin concentrations. Concomitant treatment with infliximab did not significantly affect DOX-induced changes in plasma creatinine, cystatin C, or creatinine clearance. However, infliximab significantly reduced DOX-induced action on plasma urea, NGAL, clusterin, and adiponectin. Infliximab also significantly reduced urinary albumin/creatinine ratio, NAG activity, and KIM-1 concentrations, as well as the occurrence of fibrotic lesions in kidney tissue. Fibrosis detected in the heart was unchanged. In addition, infliximab reduced DOX-induced effects on plasma inflammatory markers, renal superoxide dismutase (SOD) and total antioxidant capacity. Our results show that infliximab is partially effective in mitigating DOX-induced nephrotoxicity in rats.


Doxorubicin Infliximab Nephrotoxicity TNF-α Oxidative stress Inflammation 


Authors’ contribution

AA, YS, and BA designed research, participated in the interpretation of the results, wrote and reviewed the manuscript. NS performed the histological analysis, wrote and reviewed the manuscript. MA and PM conducted the experiments and analyzed. All authors read and approved the manuscript.

Funding information

Supported by a grant from Sultan Qaboos University (IG/MED//PHAR/16/02).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures involving animals and their care were carried out in accordance with national and international laws and policies (EEC Council directives 2010/63/EU, 22 September, 2010 and NIH Guide for the Care and Use of Laboratory Animals, NIH Publications, 8th edition, 2011).

This article does not contain any studies with human participants performed by any of the authors.


  1. Abdelrahman AM, Al Suleimani YM, Ashique M, Manoj P, Ali BH (2018) Effect of infliximab and tocilizumab on fructose-induced hyperinsulinemia and hypertension in rats. Biomed Pharmacother 105:182–186CrossRefGoogle Scholar
  2. Ali BH, Alza'abi M, Ramkumar A, Al-Lawati I, Waly MI, Beegam S, Nemmar A, Brand S, Schupp N (2014) The effect of activated charcoal on adenine-induced chronic renal failure in rats. Food Chem Toxicol 65:321–328CrossRefGoogle Scholar
  3. Cianciolo R, Yoon L, Krull D, Stokes A, Rodriguez A, Jordan H, Cooper D, Falls JG, Cullen J, Kimbrough C, Berridge B (2013) Gene expression analysis and urinary biomarker assays reveal activation of tubulointerstitial injury pathways in a rodent model of chronic proteinuria (doxorubicin nephropathy). Nephron Exp Nephrol 124:1–10CrossRefGoogle Scholar
  4. Cure E, Kirbas A, Tumkaya L, Cure MC, Kalkan Y, Yilmaz A, Yuce S (2015) Protective effect of infliximab on methotrexate-induced liver injury in rats: unexpected drug interaction. J Cancer Res Ther 11:164–169CrossRefGoogle Scholar
  5. Devarajan P (2008) NGAL in acute kidney injury: from serendipity to utility. Am J Kidney Dis 52:395–399CrossRefGoogle Scholar
  6. el Nahas AM, Bassett AH, Cope GH, Le Carpentier JE (1991) Role of growth hormone in the development of experimental renal scarring. Kidney Int 40:29–34CrossRefGoogle Scholar
  7. El-Sayed EM, Mansour AM, El-Sawy WS (2017) Protective effect of proanthocyanidins against doxorubicin-induced nephrotoxicity in rats. J Biochem Mol Toxicol 31Google Scholar
  8. El-Sheikh AA, Morsy MA, Mahmoud MM, Rifaai RA, Abdelrahman AM (2012) Effect of coenzyme-q10 on doxorubicin-induced nephrotoxicity in rats. Adv Pharmacol Sci 2012:981461Google Scholar
  9. Guo J, Guan Q, Liu X, Wang H, Gleave ME, Nguan CY, Du C (2016) Relationship of clusterin with renal inflammation and fibrosis after the recovery phase of ischemia-reperfusion injury. BMC Nephrol 17:133CrossRefGoogle Scholar
  10. Ibrahim MA, Morsy MA, Hafez HM, Gomaa WM, Abdelrahman AM (2012) Effect of selective and non-selective cyclooxygenase inhibitors on doxorubicin-induced cardiotoxicity and nephrotoxicity in rats. Toxicol Mech Methods 22:424–431CrossRefGoogle Scholar
  11. Jin X, Chen J, Hu Z, Chan L, Wang Y (2013) Genetic deficiency of adiponectin protects against acute kidney injury. Kidney Int 83:604–614CrossRefGoogle Scholar
  12. Karson A, Demirtas T, Bayramgurler D, Balci F, Utkan T (2013) Chronic administration of infliximab (TNF-alpha inhibitor) decreases depression and anxiety-like behaviour in rat model of chronic mild stress. Basic Clin Pharmacol Toxicol 112:335–340CrossRefGoogle Scholar
  13. Khames A, Khalaf MM, Gad AM, Abd El-Raouf OM (2017) Ameliorative effects of sildenafil and/or febuxostat on doxorubicin-induced nephrotoxicity in rats. Eur J Pharmacol 805:118–124CrossRefGoogle Scholar
  14. Kirbas A, Cure MC, Kalkan Y, Cure E, Tumkaya L, Sahin OZ, Yuce S, Kizilkaya B, Pergel A (2015) Effect of infliximab on renal injury due to methotrexate in rat. Iran J Kidney Dis 9:221–229Google Scholar
  15. Lee VW, Harris DC (2011) Adriamycin nephropathy: a model of focal segmental glomerulosclerosis. Nephrology (Carlton) 16:30–38CrossRefGoogle Scholar
  16. Lv W, Booz GW, Wang Y, Fan F, Roman RJ (2018) Inflammation and renal fibrosis: recent developments on key signaling molecules as potential therapeutic targets. Eur J Pharmacol 820:65–76CrossRefGoogle Scholar
  17. Mohan M, Kamble S, Gadhi P, Kasture S (2010) Protective effect of Solanum torvum on doxorubicin-induced nephrotoxicity in rats. Food Chem Toxicol 48:436–440CrossRefGoogle Scholar
  18. Moriwaki Y, Inokuchi T, Yamamoto A, Ka T, Tsutsumi Z, Takahashi S, Yamamoto T (2007) Effect of TNF-alpha inhibition on urinary albumin excretion in experimental diabetic rats. Acta Diabetol 44:215–218CrossRefGoogle Scholar
  19. Nagai K, Fukuno S, Otani K, Nagamine Y, Omotani S, Hatsuda Y, Myotoku M, Konishi H (2018) Prevention of doxorubicin-induced renal toxicity by Theanine in rats. Pharmacology 101:219–224CrossRefGoogle Scholar
  20. Oh J, Rabb H (2013) Adiponectin: an enlarging role in acute kidney injury. Kidney Int 83:546–548CrossRefGoogle Scholar
  21. Omote K, Gohda T, Murakoshi M, Sasaki Y, Kazuno S, Fujimura T, Ishizaka M, Sonoda Y, Tomino Y (2014) Role of the TNF pathway in the progression of diabetic nephropathy in KK-A(y) mice. Am J Physiol Renal Physiol 306:F1335–F1347CrossRefGoogle Scholar
  22. Rasband WS (1997-2008) ImageJ. U. S. National Institutes of Health Bethesda, Maryland, USAGoogle Scholar
  23. Rashikh A, Pillai KK, Najmi AK (2014) Protective effect of a direct renin inhibitor in acute murine model of cardiotoxicity and nephrotoxicity. Fundam Clin Pharmacol 28:489–500CrossRefGoogle Scholar
  24. Refaie MM, Amin EF, El-Tahawy NF, Abdelrahman AM (2016) Possible protective effect of Diacerein on doxorubicin-induced nephrotoxicity in rats. J Toxicol 2016:9507563CrossRefGoogle Scholar
  25. Ren X, Bo Y, Fan J, Chen M, Xu D, Dong Y, He H, Ren X, Qu R, Jin Y, Zhao W, Xu C (2016) Dalbergioidin ameliorates doxorubicin-induced renal fibrosis by suppressing the TGF-beta signal pathway. Mediat Inflamm 2016:5147571Google Scholar
  26. Saritemur M, Un H, Cadirci E, Karakus E, Akpinar E, Halici Z, Ugan RA, Karaman A, Atmaca HT (2015) Tnf-alpha inhibition by infliximab as a new target for the prevention of glycerol-contrast-induced nephropathy. Environ Toxicol Pharmacol 39:577–588CrossRefGoogle Scholar
  27. Szalay CI, Erdelyi K, Kokeny G, Lajtar E, Godo M, Revesz C, Kaucsar T, Kiss N, Sarkozy M, Csont T, Krenacs T, Szenasi G, Pacher P, Hamar P (2015) Oxidative/Nitrative stress and inflammation drive progression of doxorubicin-induced renal fibrosis in rats as revealed by comparing a Normal and a fibrosis-resistant rat strain. PLoS One 10:e0127090CrossRefGoogle Scholar
  28. Tasdemir C, Tasdemir S, Vardi N, Ates B, Parlakpinar H, Kati B, Karaaslan MG, Acet A (2012) Protective effect of infliximab on ischemia/reperfusion-induced damage in rat kidney. Ren Fail 34:1144–1149CrossRefGoogle Scholar
  29. Tian M, Tang L, Wu Y, Beddhu S, Huang Y (2018) Adiponectin attenuates kidney injury and fibrosis in deoxycorticosterone acetate-salt and angiotensin II-induced CKD mice. Am J Physiol Renal Physiol 315:F558–F571CrossRefGoogle Scholar
  30. Tulubas F, Gurel A, Oran M, Topcu B, Caglar V, Uygur E (2015) The protective effects of omega-3 fatty acids on doxorubicin-induced hepatotoxicity and nephrotoxicity in rats. Toxicol Ind Health 31:638–644CrossRefGoogle Scholar
  31. Zhang Y, Xu Y, Qi Y, Xu L, Song S, Yin L, Tao X, Zhen Y, Han X, Ma X, Liu K, Peng J (2017) Protective effects of dioscin against doxorubicin-induced nephrotoxicity via adjusting FXR-mediated oxidative stress and inflammation. Toxicology 378:53–64CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health SciencesSultan Qaboos UniversityMuscatOman
  2. 2.Institute of Toxicology, Medical FacultyUniversity of DüsseldorfDüsseldorfGermany

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