A glance at molecular mechanisms underlying cisplatin-induced nephrotoxicity and possible renoprotective strategies: a narrative review

  • Bashar Adi Wahyu Pandhita Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
  • Deliana Nur Ihsani Rahmi Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
  • Nielda Kezia Sumbung Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
  • Bernardino Matthew Waworuntu Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
  • Regina Puspa Utami Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
  • Melva Louisa Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia https://orcid.org/0000-0002-9451-0380
  • Vivian Soetikno Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
Keywords: cisplatin, kidney, kidney injury, oxidative stress


Cisplatin is a platinum-based drug that is usually used for the treatment of many carcinomas. However, it comes with several devastating side effects, including nephrotoxicity. Cisplatin toxicity is a very complex process, which is exacerbated by the accumulation of cisplatin in renal tubular cells via passive diffusion and transporter-mediated processes. Once cisplatin enters these cells, it induces the formation of reactive oxygen species that cause cellular damage, including DNA damage, inflammation, and eventually cell death. On a small scale, these damages can be mitigated by cellular antioxidant defense mechanism. However, on a large scale, such as in chemotherapy, this defense mechanism may fail, resulting in nephrotoxicity. The current article reviews the molecular mechanisms underlying cisplatin-induced nephrotoxicity and possible renoprotective strategies to determine novel therapeutic interventions for alleviating this toxicity.


Yang Y, Liu H, Liu F, Dong Z. Mitochondrial dysregulation and protection in cisplatin nephrotoxicity. Arch Toxicol. 2014;88(6):1249-56. https://doi.org/10.1007/s00204-014-1239-1

Prasaja Y, Sutandyo N, Andrajati R. Incidence of cisplatin-induced nephrotoxicity and associated factors among cancer patients in Indonesia. Asian Pac J Cancer Prev. 2015;16(3):1117-22. https://doi.org/10.7314/APJCP.2015.16.3.1117

Walker RJ, Endre ZH. Cellular mechanism of drug nephrotoxicity. In: Alpern RJ, Moe OR, Caplan MJ. Seldin and Giebisch's the kidney. 5th ed. 2013; Philadelphia: Saunders Elsevier. p.2889-932. https://doi.org/10.1016/B978-0-12-381462-3.00085-9

Pourahmad J, Hosseini MJ, Eskandari MR, Shekarabi SM, Daraei B. Mitochondrial/lysosomal toxic cross-talk plays a key role in cisplatin nephrotoxicity. Xenobiotica. 2010;40(11):763-71. https://doi.org/10.3109/00498254.2010.512093

Zsengellér ZK, Ellezian L, Brown D, Horváth B, Mukhopadhyay P, Kalyanaraman B, et al. Cisplatin nephrotoxicity involves mitochondrial injury with impaired tubular mitochondrial enzyme activity. J Histochem Cytochem. 2012;60(7):521-9. https://doi.org/10.1369/0022155412446227

Zhang JG, Lindup WE. Role of mitochondria in cisplatin-induced oxidative damage exhibited by rat renal cortical slices. Biochem Pharmacol. 1993;45(11):2215-22. https://doi.org/10.1016/0006-2952(93)90192-Y

Sari SD, Maknun LU, Louisa M, Estuningtyas A, Soetikno V. Effects of nanocurcumin against cisplatin-induced nephrotoxicity in rats. Adv Sci Lett. 2017;23(7):6823-7. https://doi.org/10.1166/asl.2017.9407

Kruidering M, Van de Water B, de Heer E, Mulder GJ, Nagelkerke JF. Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain. J Pharmacol Exp Ther. 1997;280(2):638-49.

Santos NA, Catão CS, Martins NM, Curti C, Bianchi ML, Santos AC. Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Arch Toxicol. 2007;81(7):495-504. https://doi.org/10.1007/s00204-006-0173-2

Kawai Y, Nakao T, Kunimura N, Kohda Y, Gemba M. Relationship of intracellular calcium and oxygen radicals to cisplatin-related renal cell injury. J Pharmacol Sci. 2006;100(1):65-72. https://doi.org/10.1254/jphs.FP0050661

Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanism of action. Eur J Pharmacol. 2014;740:364-78. https://doi.org/10.1016/j.ejphar.2014.07.025

Basnakian AG, Apostolov EO, Yin X, Napirei M, Mannherz HG, Shah SV. Cisplatin nephrotoxicity is mediated by deoxyribonuclease I. J Am Soc Nephrol. 2005;16(3):697-702. https://doi.org/10.1681/ASN.2004060494

Pabla N, Huang S, Mi QS, Daniel R, Dong Z. ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. J Biol Chem. 2007;283(10):6572-83. https://doi.org/10.1074/jbc.M707568200

Zhang B, Ramesh G, Norbury CC, Reeves WB. Cisplatin-induced nephrotoxicity is mediated by tumor necrosis factor-α produced by renal parenchymal cells. Kidney Int. 2007;72(1):37-44. https://doi.org/10.1038/sj.ki.5002242

Gluba A, Banach M, Hannam S, Mikhailidis DP, Sakowicz A, Rysz J. The role of Toll-like receptors in renal diseases. Nat Rev Nephrol. 2010;6(4):224-35. https://doi.org/10.1038/nrneph.2010.16

Kelly KJ, Meehan SM, Colvin RB, Williams WW, Bonventre JV. Protection from toxicant-mediated renal injury in the rat with anti-CD54 antibody. Kidney Int. 1999;56(3):922-31. https://doi.org/10.1046/j.1523-1755.1999.00629.x

Deng J, Kohda Y, Chiao H, Wang Y, Hu X, Hewitt SM, et al. Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney Int. 2001;60(6):2118-28. https://doi.org/10.1046/j.1523-1755.2001.00043.x

Ramesh G, Reeves WB. TNF-α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest. 2002;110(6):835-42. https://doi.org/10.1172/JCI200215606

Mahgoub E, Kumaraswamy SM, Kader KH, Venkataraman B, Ojha S, Adeghate E, et al. Genipin attenuates cisplatin-induced nephrotoxicity by counteracting oxidative stress, inflammation, and apoptosis. Biomed Pharmacother. 2017;93:1083-97. https://doi.org/10.1016/j.biopha.2017.07.018

Soetikno V, Sari SD, Maknun LU, Sumbung NK, Rahmi DN, Pandhita BA, et al. Pre-treatment with curcumin ameliorates cisplatin-induced kidney damage by suppressing kidney inflammation and apoptosis in rats. Drug Res. 2018;69(2):75-82. https://doi.org/10.1055/a-0641-5148

Ramesh G, Reeves WB. Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-α. Kidney Int. 2004;65(2):490-8. https://doi.org/10.1111/j.1523-1755.2004.00413.x

Ramesh G, Reeves WB. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Renal Physiol. 2005;289(1):F166-74. https://doi.org/10.1152/ajprenal.00401.2004

Barbara JA, Smith WB, Gamble JR, Van Ostade X, Vandenabeele P, Tavernier J, et al. Dissociation of TNF-α cytotoxic and proinflammatory activities by p55 receptor- and p75 receptorselective TNF-α mutants. EMBO J. 1994;13(4):843-50. https://doi.org/10.1002/j.1460-2075.1994.tb06327.x

Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001;104(4):487-501. https://doi.org/10.1016/S0092-8674(01)00237-9

Ramesh G, Reeves WB. TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure. Am J Physiol Renal Physiol. 2003;285(4):F610-8. https://doi.org/10.1152/ajprenal.00101.2003

Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol. 2008;8(4):279-89. https://doi.org/10.1038/nri2215

Cunningham PN, Wang Y, Guo R, He G, Quigg RJ. Role of Toll-like receptor 4 in endotoxin-induced acute renal failure. J Immunol. 2004;172(4):2629-35. https://doi.org/10.4049/jimmunol.172.4.2629

Ramesh G, Zhang B, Uematsu S, Akira S, Reeves WB. Endotoxin and cisplatin synergistically induce renal dysfunction and cytokine production in mice. Am J Physiol Renal Physiol. 2007;293(1):F325-32. https://doi.org/10.1152/ajprenal.00158.2007

Ramesh G, Kimball SR, Jefferson LS, Reeves WB. Endotoxin and cisplatin synergistically stimulate TNF-α production by renal epithelial cells. Am J Physiol Renal Physiol. 2007;292(2):F812-9. https://doi.org/10.1152/ajprenal.00277.2006

Zhang B, Ramesh G, Uematsu S, Akira S, Reeves WB. TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. J Am Soc Nephrol. 2008;19(5):923-32. https://doi.org/10.1681/ASN.2007090982

Tsung A, Klune JR, Zhang X, Jeyabalan G, Cao Z, Peng X, et al. HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. J Exp Med. 2007;204(12):2913-23. https://doi.org/10.1084/jem.20070247

Lieberthal W, Triaca V, Levine J. Mechanism of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis. Am J Physiol. 1996;270 (4):F700-8. https://doi.org/10.1152/ajprenal.1996.270.4.F700

Hong JY, Kim GH, Kim JW, Kwon SS, Sato EF, Cho KH, et al. Computational modeling of apoptotic signaling pathways induced by cisplatin. BMC Syst Biol. 2012;6:122. https://doi.org/10.1186/1752-0509-6-122

Tsuruya K, Ninomiya T, Tokumoto M, Hirakawa M, Masutani K, Taniguchi M, et al. Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Kidney Int. 2003;63(1):72-82. https://doi.org/10.1046/j.1523-1755.2003.00709.x

Wei Q, Dong G, Yang T, Megyesi J, Price PM, Dong Z. Activation and involvement of p53 in cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol. 2007;293(4):F1282-91. https://doi.org/10.1152/ajprenal.00230.2007

Tsuruya K, Yotsueda H, Ikeda H, Taniguchi M, Masutani K, Hayashida H, et al. Involvement of p53-transactivated Puma in cisplatin-induced renal tubular cell death. Life Sci. 2008;83(151-6):550-6. https://doi.org/10.1016/j.lfs.2008.08.002

Zhang D, Liu Y, Wei Q, Huo Y, Liu K, Liu F, et al. Tubular p53 regulates multiple genes to mediate AKI. J Am Soc Nephrol. 2014;25(10):2278-89. https://doi.org/10.1681/ASN.2013080902

Follis AV, Chipuk JE, Fisher JC, Yun MK, Grace CR, Nourse A, et al. PUMA binding induces partial unfolding within BCL-xL to disrupt p53 binding and promote apoptosis. Nat Chem Biol. 2013;9(3):163-8. https://doi.org/10.1038/nchembio.1166

di Pietro A, Koster R, Boersma-van Eck W, Dam WA, Mulder NH, Gietema JA, et al. Pro- and anti-apoptotic effects of p53 in cisplatin-treated human testicular cancer are cell contextdependent. Cell Cycle. 2012;11(24):4552-62. https://doi.org/10.4161/cc.22803

Hodeify R, Tarcsafalvi A, Megyesi J, Safirstein RL, Price PM. Cdk2-dependent phosphorylation of p21 regulates the role of Cdk2 in cisplatin cytotoxicity. Am J Physiol Renal Physiol. 2011;300(5):F1171-9. https://doi.org/10.1152/ajprenal.00507.2010

Kawai Y, Tainuchi S, Okahara S, Nakamura M, Gemba M. Relationship between cisplatin or nedaplatin-induced nephrotoxicity and renal accumulation. Biol Pharm Bull. 2005;28(8):1385-8. https://doi.org/10.1248/bpb.28.1385

Esteban-Fernández D, Verdaguer JM, Ramírez-Camacho R, Palacios MA, Gómez-Gómez MM. Accumulation, fractionation, and analysis of platinum in toxicologically affected tissues after cisplatin, oxaliplatin, and carboplatin administration. J Anal Toxicol. 2008;32(2):140-6. https://doi.org/10.1093/jat/32.2.140

Kröning R, Lichtenstein AK, Nagami GT. Sulfur-containing amino acids decrease cisplatin cytotoxicity and uptake in renal tubule epithelial cell lines. Cancer Chemother Pharmacol. 2000;45(1):43-9. https://doi.org/10.1007/PL00006741

Endo T, Kimura O, Sakata M. Carrier-mediated uptake of cisplatin by the OK renal epithelial cell line. Toxicology. 2000;146(2-3):187-95. https://doi.org/10.1016/S0300-483X(00)00176-1

Pabla N, Murphy RF, Liu K, Dong Z. The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity. Am J Physiol Renal Physiol. 2009;296(3):F505-11. https://doi.org/10.1152/ajprenal.90545.2008

Jacobs C, Kalman SM, Tretton M, Weiner MW. Renal handling of cis-diamminedichloroplatinum (II). Cancer Treat Rep. 1980;64(12):1223-6.

Osman NM, Litterst CL. Effect of probenecid and N'-methylnicotinamide on renal handling of cisdichlorodiammineplatinum-II in rats. Cancer Lett. 1983;19(1):107-11. https://doi.org/10.1016/0304-3835(83)90143-X

Bird JE, Walser MM, Quebbemann AJ. Protective effect of organic cation transport inhibitors on cis-diamminedichloroplatinum induced nephrotoxicity. J Pharmacol Exp Ther. 1984;231(3):752-8.

Klein J, Bentur Y, Cheung D, Moselhy G, Koren G. Renal handling of cisplatin: interactions with organic anions and cations in the dog. Clin Invest Med. 1991;14(5):388-94.

Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, et al. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 1997;16(7):871-81. https://doi.org/10.1089/dna.1997.16.871

Ciarimboli G, Ludwig T, Lang D, Pavenstäd H, Koepsell H, Piechota HJ, et al. Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. Am J Pathol. 2005;167(6):1477-84. https://doi.org/10.1016/S0002-9440(10)61234-5

Ishida S, Lee J, Thiele DJ, Herskowitz I. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci U S A. 2002;99(22):14298-302. https://doi.org/10.1073/pnas.162491399

Yang C, Kaushal V, Shah SV, Kaushal GP. Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells. Am J Physiol Renal Physiol. 2008;294(4):F777-87. https://doi.org/10.1152/ajprenal.00590.2007

Takahashi A, Kimura T, Takabatake Y, Namba T, Kaimori J, Kitamura H, et al. Autophagy guards against cisplatin-induced acute kidney injury. Am J Pathol. 2012;180(2):517-25. https://doi.org/10.1016/j.ajpath.2011.11.001

Zhang D, Pan J, Xiang X, Liu Y, Dong G, Livingston MJ, et al. Protein kinase cδ suppresses autophagy to induce kidney cell apoptosis in cisplatin nephrotoxicity. J Am Soc Nephrol. 2017;28(4):1131-44. https://doi.org/10.1681/ASN.2016030337

Zhao C, Chen Z, Xu X, An X, Duan S, Huang Z, et al. Pink1/Parkin-mediated mitophagy play a protective role in cisplatin induced renal tubular epithelial cells injury. Exp Cell Res. 2017;350(2):390-7. https://doi.org/10.1016/j.yexcr.2016.12.015

Wilmes A, Bielow C, Ranninger C, Bellwon P, Aschauer L, Limonciel A, et al. Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015;30(1 Pt A):117-27. https://doi.org/10.1016/j.tiv.2014.10.006

How to Cite
Pandhita BAW, Rahmi DNI, Sumbung NK, Waworuntu BM, Utami RP, Louisa M, Soetikno V. A glance at molecular mechanisms underlying cisplatin-induced nephrotoxicity and possible renoprotective strategies: a narrative review. Med J Indones [Internet]. 2019Oct.4 [cited 2024Feb.26];28(3):292-9. Available from: https://mji.ui.ac.id/journal/index.php/mji/article/view/2690
Review Article

Most read articles by the same author(s)