Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cisplatin nephrotoxicity: new insights and therapeutic implications

Nature Reviews Nephrology volume 19, pages 53–72 (2023)Cite this article

Subjects

Abstract

Cisplatin is an effective chemotherapeutic agent for various solid tumours, but its use is limited by adverse effects in normal tissues. In particular, cisplatin is nephrotoxic and can cause acute kidney injury and chronic kidney disease. Preclinical studies have provided insights into the cellular and molecular mechanisms of cisplatin nephrotoxicity, which involve intracellular stresses including DNA damage, mitochondrial pathology, oxidative stress and endoplasmic reticulum stress. Stress responses, including autophagy, cell-cycle arrest, senescence, apoptosis, programmed necrosis and inflammation have key roles in the pathogenesis of cisplatin nephrotoxicity. In addition, emerging evidence suggests a contribution of epigenetic changes to cisplatin-induced acute kidney injury and chronic kidney disease. Further research is needed to determine how these pathways are integrated and to identify the cell type-specific roles of critical molecules involved in regulated necrosis, inflammation and epigenetic modifications in cisplatin nephrotoxicity. A number of potential therapeutic targets for cisplatin nephrotoxicity have been identified. However, the effects of renoprotective strategies on the efficacy of cisplatin chemotherapy needs to be thoroughly evaluated. Further research using tumour-bearing animals, multi-omics and genome-wide association studies will enable a comprehensive understanding of the complex cellular and molecular mechanisms of cisplatin nephrotoxicity and potentially lead to the identification of specific targets to protect the kidney without compromising the chemotherapeutic efficacy of cisplatin.

Key points

  • Cisplatin is nephrotoxin that can cause both acute kidney injury and chronic kidney disease.

  • Accumulation of cisplatin in renal tubular cells induces various intracellular stresses, including DNA damage, mitochondrial pathology, oxidative stress and endoplasmic reticulum stress.

  • Multiple stress responses, including autophagy, cell-cycle arrest, senescence, apoptosis, programmed necrosis and inflammation, have important roles in the pathogenesis of cisplatin nephrotoxicity.

  • Epigenetic mechanisms, including histone acetylation, DNA and messenger RNA methylation and gene regulation by non-coding RNAs also contribute to cisplatin nephrotoxicity.

  • How the various cellular stresses and pathways are integrated and the cell type-specific roles of critical molecules involved in regulated necrosis, inflammation and epigenetic modifications in cisplatin nephrotoxicity remain to be determined.

  • Renoprotective strategies for cisplatin nephrotoxicity have been identified in preclinical studies; however, their effects on the efficacy of cisplatin-mediated cancer therapy in animal models must be evaluated before clinical translation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The pathophysiology of cisplatin nephrotoxicity.
Fig. 2: Cell-cycle regulation and senescence in cisplatin nephrotoxicity.
Fig. 3: Apoptotic pathways in cisplatin nephrotoxicity.
Fig. 4: Pathways of regulated necrosis in cisplatin nephrotoxicity.
Fig. 5: Pattern recognition receptor signalling in cisplatin nephrotoxicity.

Similar content being viewed by others

References

  1. Dasari, S. & Tchounwou, P. B. Cisplatin in cancer therapy: molecular mechanisms of action. Eur. J. Pharmacol. 740, 364–378 (2014).

    Article  CAS  Google Scholar 

  2. Klumpers, M. J. et al. Genome-wide analyses of nephrotoxicity in platinum-treated cancer patients identify association with genetic variant in RBMS3 and acute kidney injury. J. Pers. Med. 12, 892 (2022).

    Article  Google Scholar 

  3. Volarevic, V. et al. Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity. J. Biomed. Sci. 26, 25 (2019).

    Article  Google Scholar 

  4. Miller, R. P., Tadagavadi, R. K., Ramesh, G. & Reeves, W. B. Mechanisms of cisplatin nephrotoxicity. Toxins 2, 2490–2518 (2010).

    Article  CAS  Google Scholar 

  5. Latcha, S. et al. Long-term renal outcomes after cisplatin treatment. Clin. J. Am. Soc. Nephrol. 11, 1173–1179 (2016).

    Article  CAS  Google Scholar 

  6. Holditch, S. J., Brown, C. N., Lombardi, A. M., Nguyen, K. N. & Edelstein, C. L. Recent advances in models, mechanisms, biomarkers, and interventions in cisplatin-induced acute kidney injury. Int. J. Mol. Sci. 20, 3011 (2019).

    Article  CAS  Google Scholar 

  7. Katagiri, D. et al. Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition. Kidney Int. 89, 374–385 (2016).

    Article  CAS  Google Scholar 

  8. Sharp, C. N. et al. Repeated administration of low-dose cisplatin in mice induces fibrosis. Am. J. Physiol. Renal Physiol. 310, F560–F568 (2016).

    Article  CAS  Google Scholar 

  9. Torres, R. et al. Three-dimensional morphology by multiphoton microscopy with clearing in a model of cisplatin-induced CKD. J. Am. Soc. Nephrol. 27, 1102–1112 (2016).

    Article  CAS  Google Scholar 

  10. Sharp, C. N. et al. Subclinical kidney injury induced by repeated cisplatin administration results in progressive chronic kidney disease. Am. J. Physiol. Renal Physiol. 315, F161–F172 (2018).

    Article  CAS  Google Scholar 

  11. Fu, Y. et al. Chronic effects of repeated low-dose cisplatin treatment in mouse kidneys and renal tubular cells. Am. J. Physiol. Renal Physiol. 317, F1582–F1592 (2019).

    Article  CAS  Google Scholar 

  12. Landau, S. I. et al. Regulated necrosis and failed repair in cisplatin-induced chronic kidney disease. Kidney Int. 95, 797–814 (2019).

    Article  CAS  Google Scholar 

  13. Menshikh, A. et al. Capillary rarefaction is more closely associated with CKD progression after cisplatin, rhabdomyolysis, and ischemia-reperfusion-induced AKI than renal fibrosis. Am. J. Physiol. Renal Physiol. 317, F1383–F1397 (2019).

    Article  CAS  Google Scholar 

  14. Sears, S. M. et al. C57BL/6 mice require a higher dose of cisplatin to induce renal fibrosis and CCL2 correlates with cisplatin-induced kidney injury. Am. J. Physiol. Renal Physiol. 319, F674–F685 (2020).

    Article  CAS  Google Scholar 

  15. Black, L. M. et al. Divergent effects of AKI to CKD models on inflammation and fibrosis. Am. J. Physiol. Renal Physiol. 315, F1107–F1118 (2018).

    Article  CAS  Google Scholar 

  16. Sharp, C. N., Doll, M., Dupre, T. V., Beverly, L. J. & Siskind, L. J. Moderate aging does not exacerbate cisplatin-induced kidney injury or fibrosis despite altered inflammatory cytokine expression and immune cell infiltration. Am. J. Physiol. Renal Physiol. 316, F162–F172 (2019).

    Article  CAS  Google Scholar 

  17. Fujishiro, H., Taguchi, H., Hamao, S., Sumi, D. & Himeno, S. Comparisons of segment-specific toxicity of platinum-based agents and cadmium using S1, S2, and S3 cells derived from mouse kidney proximal tubules. Toxicol. Vitr. 75, 105179 (2021).

    Article  CAS  Google Scholar 

  18. Filipski, K. K., Mathijssen, R. H., Mikkelsen, T. S., Schinkel, A. H. & Sparreboom, A. Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin. Pharmacol. Ther. 86, 396–402 (2009).

    Article  CAS  Google Scholar 

  19. Ciarimboli, G. et al. Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am. J. Pathol. 176, 1169–1180 (2010).

    Article  CAS  Google Scholar 

  20. Guo, D. et al. Selective inhibition on organic cation transporters by carvedilol protects mice from cisplatin-induced nephrotoxicity. Pharm. Res. 35, 204 (2018).

    Article  Google Scholar 

  21. Hu, S. et al. Identification of OAT1/OAT3 as contributors to cisplatin toxicity. Clin. Transl. Sci. 10, 412–420 (2017).

    Article  CAS  Google Scholar 

  22. Pabla, N., Murphy, R. F., Liu, K. & Dong, Z. The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity. Am. J. Physiol. Renal Physiol. 296, F505–F511 (2009).

    Article  CAS  Google Scholar 

  23. Wen, X. et al. Transgenic expression of the human MRP2 transporter reduces cisplatin accumulation and nephrotoxicity in Mrp2-null mice. Am. J. Pathol. 184, 1299–1308 (2014).

    Article  CAS  Google Scholar 

  24. Nakamura, T., Yonezawa, A., Hashimoto, S., Katsura, T. & Inui, K. Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity. Biochem. Pharmacol. 80, 1762–1767 (2010).

    Article  CAS  Google Scholar 

  25. Mizuno, T. et al. Significance of downregulation of renal organic cation transporter (SLC47A1) in cisplatin-induced proximal tubular injury. Onco Targets Ther. 8, 1701–1706 (2015).

    Article  Google Scholar 

  26. Ciarimboli, G. Membrane transporters as mediators of cisplatin side-effects. Anticancer. Res. 34, 547–550 (2014).

    CAS  Google Scholar 

  27. Katsuda, H. et al. Protecting cisplatin-induced nephrotoxicity with cimetidine does not affect antitumor activity. Biol. Pharm. Bull. 33, 1867–1871 (2010).

    Article  CAS  Google Scholar 

  28. Iwata, K. et al. Effects of genetic variants in SLC22A2 organic cation transporter 2 and SLC47A1 multidrug and toxin extrusion 1 transporter on cisplatin-induced adverse events. Clin. Exp. Nephrol. 16, 843–851 (2012).

    Article  CAS  Google Scholar 

  29. Zhang, J. & Zhou, W. Ameliorative effects of SLC22A2 gene polymorphism 808 G/T and cimetidine on cisplatin-induced nephrotoxicity in Chinese cancer patients. Food Chem. Toxicol. 50, 2289–2293 (2012).

    Article  CAS  Google Scholar 

  30. Ghonaim, E., El-Haggar, S. & Gohar, S. Possible protective effect of pantoprazole against cisplatin-induced nephrotoxicity in head and neck cancer patients: a randomized controlled trial. Med. Oncol. 38, 108 (2021).

    Article  CAS  Google Scholar 

  31. Fox, E. et al. Pantoprazole, an inhibitor of the organic cation transporter 2, does not ameliorate cisplatin-related ototoxicity or nephrotoxicity in children and adolescents with newly diagnosed osteosarcoma treated with methotrexate, doxorubicin, and cisplatin. Oncologist 23, 762–e779 (2018).

    Article  CAS  Google Scholar 

  32. Solanki, M. H. et al. Magnesium protects against cisplatin-induced acute kidney injury without compromising cisplatin-mediated killing of an ovarian tumor xenograft in mice. Am. J. Physiol. Renal Physiol. 309, F35–F47 (2015).

    Article  CAS  Google Scholar 

  33. Kumar, G. et al. Magnesium improves cisplatin-mediated tumor killing while protecting against cisplatin-induced nephrotoxicity. Am. J. Physiol. Renal Physiol. 313, F339–F350 (2017).

    Article  CAS  Google Scholar 

  34. Saito, Y. et al. Magnesium attenuates cisplatin-induced nephrotoxicity by regulating the expression of renal transporters. Eur. J. Pharmacol. 811, 191–198 (2017).

    Article  CAS  Google Scholar 

  35. Kimura, T. et al. Renal protective effect of a hydration supplemented with magnesium in patients receiving cisplatin for head and neck cancer. J. Otolaryngol. Head. Neck Surg. 47, 10 (2018).

    Article  Google Scholar 

  36. Yamamoto, Y. et al. Nephroprotective effects of hydration with magnesium in patients with cervical cancer receiving cisplatin. Anticancer. Res. 35, 2199–2204 (2015).

    CAS  Google Scholar 

  37. Saito, Y. et al. Premedication with intravenous magnesium has a protective effect against cisplatin-induced nephrotoxicity. Support. Care Cancer 25, 481–487 (2017).

    Article  Google Scholar 

  38. Saito, Y. et al. Magnesium co-administration decreases cisplatin-induced nephrotoxicity in the multiple cisplatin administration. Life Sci. 189, 18–22 (2017).

    Article  CAS  Google Scholar 

  39. Townsend, D. M., Deng, M., Zhang, L., Lapus, M. G. & Hanigan, M. H. Metabolism of cisplatin to a nephrotoxin in proximal tubule cells. J. Am. Soc. Nephrol. 14, 1–10 (2003).

    Article  CAS  Google Scholar 

  40. Hanigan, M. H. et al. Gamma-glutamyl transpeptidase-deficient mice are resistant to the nephrotoxic effects of cisplatin. Am. J. Pathol. 159, 1889–1894 (2001).

    Article  CAS  Google Scholar 

  41. Hanigan, M. H., Gallagher, B. C., Taylor, P. T. Jr & Large, M. K. Inhibition of gamma-glutamyl transpeptidase activity by acivicin in vivo protects the kidney from cisplatin-induced toxicity. Cancer Res. 54, 5925–5929 (1994).

    CAS  Google Scholar 

  42. Townsend, D. M. & Hanigan, M. H. Inhibition of gamma-glutamyl transpeptidase or cysteine S-conjugate beta-lyase activity blocks the nephrotoxicity of cisplatin in mice. J. Pharmacol. Exp. Ther. 300, 142–148 (2002).

    Article  CAS  Google Scholar 

  43. Basu, A. & Krishnamurthy, S. Cellular responses to cisplatin-induced DNA damage. J. Nucleic Acids 2010, 201367 (2010).

    Article  Google Scholar 

  44. Wang, D. & Lippard, S. J. Cellular processing of platinum anticancer drugs. Nat. Rev. Drug Discov. 4, 307–320 (2005).

    Article  CAS  Google Scholar 

  45. Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).

    Article  CAS  Google Scholar 

  46. Khrunin, A. et al. Pharmacogenomics of cisplatin-based chemotherapy in ovarian cancer patients of different ethnic origins. Pharmacogenomics 13, 171–178 (2012).

    Article  CAS  Google Scholar 

  47. Tzvetkov, M. V. et al. Pharmacogenetic analyses of cisplatin-induced nephrotoxicity indicate a renoprotective effect of ERCC1 polymorphisms. Pharmacogenomics 12, 1417–1427 (2011).

    Article  CAS  Google Scholar 

  48. Zazuli, Z. et al. Outcome definition influences the relationship between genetic polymorphisms of ERCC1, ERCC2, SLC22A2 and cisplatin nephrotoxicity in adult testicular cancer patients. Genes 10, 364 (2019).

    Article  CAS  Google Scholar 

  49. Zazuli, Z. et al. Genetic variations and cisplatin nephrotoxicity: a systematic review. Front. Pharmacol. 9, 1111 (2018).

    Article  CAS  Google Scholar 

  50. Morizane, R. et al. Nephron organoids derived from human pluripotent stem cells model kidney development and injury. Nat. Biotechnol. 33, 1193–1200 (2015).

    Article  CAS  Google Scholar 

  51. Pabla, N., Huang, S., Mi, Q. S., Daniel, R. & Dong, Z. ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. J. Biol. Chem. 283, 6572–6583 (2008).

    Article  CAS  Google Scholar 

  52. Kishi, S. et al. Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses. J. Clin. Invest. 129, 4797–4816 (2019).

    Article  CAS  Google Scholar 

  53. Wang, J. et al. Caspase-mediated cleavage of ATM during cisplatin-induced tubular cell apoptosis: inactivation of its kinase activity toward p53. Am. J. Physiol. Renal Physiol. 291, F1300–F1307 (2006).

    Article  CAS  Google Scholar 

  54. Uehara, M. et al. Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice. Sci. Rep. 10, 4441 (2020).

    Article  CAS  Google Scholar 

  55. Yan, M., Tang, C., Ma, Z., Huang, S. & Dong, Z. DNA damage response in nephrotoxic and ischemic kidney injury. Toxicol. Appl. Pharmacol. 313, 104–108 (2016).

    Article  CAS  Google Scholar 

  56. Yamashita, N. et al. Cumulative DNA damage by repeated low-dose cisplatin injection promotes the transition of acute to chronic kidney injury in mice. Sci. Rep. 11, 20920 (2021).

    Article  CAS  Google Scholar 

  57. Gupta, N. et al. Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair. Sci. Transl. Med. 14, eabj4772 (2022).

    Article  CAS  Google Scholar 

  58. Rundle, S., Bradbury, A., Drew, Y. & Curtin, N. J. Targeting the ATR-CHK1 axis in cancer therapy. Cancers 9, 41 (2017).

    Article  Google Scholar 

  59. Tang, C. et al. Mitochondrial quality control in kidney injury and repair. Nat. Rev. Nephrol. 17, 299–318 (2021).

    Article  CAS  Google Scholar 

  60. Brooks, C., Wei, Q., Cho, S. G. & Dong, Z. Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J. Clin. Invest. 119, 1275–1285 (2009).

    Article  CAS  Google Scholar 

  61. Morigi, M. et al. Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury. J. Clin. Invest. 125, 715–726 (2015).

    Article  Google Scholar 

  62. Liu, Z. et al. Numb depletion promotes Drp1-mediated mitochondrial fission and exacerbates mitochondrial fragmentation and dysfunction in acute kidney injury. Antioxid. Redox Signal. 30, 1797–1816 (2019).

    Article  CAS  Google Scholar 

  63. Chang, C. R. & Blackstone, C. Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann. N. Y. Acad. Sci. 1201, 34–39 (2010).

    Article  CAS  Google Scholar 

  64. Yuan, L. et al. PGC-1alpha alleviates mitochondrial dysfunction via TFEB-mediated autophagy in cisplatin-induced acute kidney injury. Aging 13, 8421–8439 (2021).

    Article  CAS  Google Scholar 

  65. Lu, Q. et al. Rheb1 protects against cisplatin-induced tubular cell death and acute kidney injury via maintaining mitochondrial homeostasis. Cell Death Dis. 11, 364 (2020).

    Article  CAS  Google Scholar 

  66. Oh, C. J. et al. Pyruvate dehydrogenase kinase 4 deficiency attenuates cisplatin-induced acute kidney injury. Kidney Int. 91, 880–895 (2017).

    Article  CAS  Google Scholar 

  67. Yang, S. K. et al. Mitochondria targeted peptide SS-31 prevent on cisplatin-induced acute kidney injury via regulating mitochondrial ROS-NLRP3 pathway. Biomed. Pharmacother. 130, 110521 (2020).

    Article  CAS  Google Scholar 

  68. Hu, Y. et al. Cisplatin-mediated upregulation of APE2 binding to MYH9 provokes mitochondrial fragmentation and acute kidney injury. Cancer Res. 81, 713–723 (2021).

    Article  CAS  Google Scholar 

  69. Chung, K. W. et al. Mitochondrial damage and activation of the STING pathway lead to renal inflammation and fibrosis. Cell Metab. 30, 784–799 e785 (2019).

    Article  CAS  Google Scholar 

  70. Wang, Y. et al. PINK1/Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity to protect against kidney injury. Cell Death Dis. 9, 1113 (2018).

    Article  Google Scholar 

  71. Fujii, R. et al. Decreased IFT88 expression with primary cilia shortening causes mitochondrial dysfunction in cisplatin-induced tubular injury. Am. J. Physiol. Renal Physiol. 321, F278–F292 (2021).

    Article  CAS  Google Scholar 

  72. Wang, S., Zhuang, S. & Dong, Z. IFT88 deficiency in proximal tubular cells exaggerates cisplatin-induced injury by suppressing autophagy. Am. J. Physiol. Renal Physiol. 321, F269–F277 (2021).

    Article  CAS  Google Scholar 

  73. Mapuskar, K. A. et al. Persistent increase in mitochondrial superoxide mediates cisplatin-induced chronic kidney disease. Redox Biol. 20, 98–106 (2019).

    Article  CAS  Google Scholar 

  74. Quintanilha, J. C. F. et al. Involvement of cytochrome P450 in cisplatin treatment: implications for toxicity. Cancer Chemother. Pharmacol. 80, 223–233 (2017).

    Article  CAS  Google Scholar 

  75. Pabla, N. & Dong, Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. 73, 994–1007 (2008).

    Article  CAS  Google Scholar 

  76. Hasegawa, K. et al. Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function. J. Biol. Chem. 285, 13045–13056 (2010).

    Article  CAS  Google Scholar 

  77. Chiba, T. et al. Sirtuin 5 regulates proximal tubule fatty acid oxidation to protect against AKI. J. Am. Soc. Nephrol. 30, 2384–2398 (2019).

    Article  CAS  Google Scholar 

  78. Dutta, R. K. et al. Beneficial effects of myo-inositol oxygenase deficiency in cisplatin-induced AKI. J. Am. Soc. Nephrol. 28, 1421–1436 (2017).

    Article  CAS  Google Scholar 

  79. Xiao, W., Wang, R. S., Handy, D. E. & Loscalzo, J. NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxid. Redox Signal. 28, 251–272 (2018).

    Article  CAS  Google Scholar 

  80. Oh, G. S. et al. Pharmacological activation of NQO1 increases NAD+ levels and attenuates cisplatin-mediated acute kidney injury in mice. Kidney Int. 85, 547–560 (2014).

    Article  CAS  Google Scholar 

  81. Tran, M. T. et al. PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature 531, 528–532 (2016).

    Article  CAS  Google Scholar 

  82. Katsyuba, E. et al. De novo NAD+ synthesis enhances mitochondrial function and improves health. Nature 563, 354–359 (2018).

    Article  CAS  Google Scholar 

  83. Meng, X. M. et al. NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation. Lab. Invest. 98, 63–78 (2018).

    Article  CAS  Google Scholar 

  84. Casanova, A. G. et al. A meta-analysis of preclinical studies using antioxidants for the prevention of cisplatin nephrotoxicity: implications for clinical application. Crit. Rev. Toxicol. 50, 780–800 (2020).

    Article  CAS  Google Scholar 

  85. Mukhopadhyay, P. et al. Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy. Free. Radic. Biol. Med. 52, 497–506 (2012).

    Article  CAS  Google Scholar 

  86. Suzuki, T. et al. Mitochonic acid 5 binds mitochondria and ameliorates renal tubular and cardiac myocyte damage. J. Am. Soc. Nephrol. 27, 1925–1932 (2016).

    Article  CAS  Google Scholar 

  87. Sanchez-Gonzalez, P. D. et al. Differential effect of quercetin on cisplatin-induced toxicity in kidney and tumor tissues. Food Chem. Toxicol. 107, 226–236 (2017).

    Article  CAS  Google Scholar 

  88. Sanchez-Gonzalez, P. D., Lopez-Hernandez, F. J., Perez-Barriocanal, F., Morales, A. I. & Lopez-Novoa, J. M. Quercetin reduces cisplatin nephrotoxicity in rats without compromising its anti-tumour activity. Nephrol. Dial. Transpl. 26, 3484–3495 (2011).

    Article  CAS  Google Scholar 

  89. Orsolic, N. & Car, N. Quercetin and hyperthermia modulate cisplatin-induced DNA damage in tumor and normal tissues in vivo. Tumour Biol. 35, 6445–6454 (2014).

    Article  CAS  Google Scholar 

  90. Li, C., Shen, Y., Huang, L., Liu, C. & Wang, J. Senolytic therapy ameliorates renal fibrosis postacute kidney injury by alleviating renal senescence. FASEB J. 35, e21229 (2021).

    CAS  Google Scholar 

  91. Hetz, C., Zhang, K. & Kaufman, R. J. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol. 21, 421–438 (2020).

    Article  CAS  Google Scholar 

  92. Huang, Z. et al. Activation of GPR120 by TUG891 ameliorated cisplatin-induced acute kidney injury via repressing ER stress and apoptosis. Biomed. Pharmacother. 126, 110056 (2020).

    Article  CAS  Google Scholar 

  93. Peyrou, M., Hanna, P. E. & Cribb, A. E. Cisplatin, gentamicin, and p-aminophenol induce markers of endoplasmic reticulum stress in the rat kidneys. Toxicol. Sci. 99, 346–353 (2007).

    Article  CAS  Google Scholar 

  94. Yan, M., Shu, S., Guo, C., Tang, C. & Dong, Z. Endoplasmic reticulum stress in ischemic and nephrotoxic acute kidney injury. Ann. Med. 50, 381–390 (2018).

    Article  CAS  Google Scholar 

  95. Kim, H. J., Yoon, Y. M., Lee, J. H. & Lee, S. H. Protective role of fucoidan on cisplatin-mediated ER stress in renal proximal tubule epithelial cells. Anticancer. Res. 39, 5515–5524 (2019).

    Article  CAS  Google Scholar 

  96. Chen, B. et al. Epigallocatechin-3-gallate protects against cisplatin-induced nephrotoxicity by inhibiting endoplasmic reticulum stress-induced apoptosis. Exp. Biol. Med. 240, 1513–1519 (2015).

    Article  CAS  Google Scholar 

  97. Hao, Y. et al. 2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury. Biosci. Rep. 40, BSR20191538 (2020).

    Article  CAS  Google Scholar 

  98. Kong, D. et al. Erythropoietin protects against cisplatin-induced nephrotoxicity by attenuating endoplasmic reticulum stress-induced apoptosis. J. Nephrol. 26, 219–227 (2013).

    Article  CAS  Google Scholar 

  99. Peyrou, M. & Cribb, A. E. Effect of endoplasmic reticulum stress preconditioning on cytotoxicity of clinically relevant nephrotoxins in renal cell lines. Toxicol. Vitr. 21, 878–886 (2007).

    Article  CAS  Google Scholar 

  100. Shu, S. et al. Endoplasmic reticulum stress contributes to cisplatin-induced chronic kidney disease via the PERK-PKCδ pathway. Cell Mol. Life Sci. 79, 452 (2022).

    Article  CAS  Google Scholar 

  101. Periyasamy-Thandavan, S. et al. Autophagy is cytoprotective during cisplatin injury of renal proximal tubular cells. Kidney Int. 74, 631–640 (2008).

    Article  CAS  Google Scholar 

  102. Yang, C., Kaushal, V., Shah, S. V. & Kaushal, G. P. Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells. Am. J. Physiol. Renal Physiol. 294, F777–F787 (2008).

    Article  CAS  Google Scholar 

  103. Inoue, K. et al. Cisplatin-induced macroautophagy occurs prior to apoptosis in proximal tubules in vivo. Clin. Exp. Nephrol. 14, 112–122 (2010).

    Article  CAS  Google Scholar 

  104. Jiang, M. et al. Autophagy in proximal tubules protects against acute kidney injury. Kidney Int. 82, 1271–1283 (2012).

    Article  CAS  Google Scholar 

  105. Takahashi, A. et al. Autophagy guards against cisplatin-induced acute kidney injury. Am. J. Pathol. 180, 517–525 (2012).

    Article  CAS  Google Scholar 

  106. Hu, X., Ma, Z., Wen, L., Li, S. & Dong, Z. Autophagy in cisplatin nephrotoxicity during cancer therapy. Cancers 13, 5618 (2021).

    Article  CAS  Google Scholar 

  107. Liu, J. et al. Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells. Cell Death Dis. 9, 322 (2018).

    Article  CAS  Google Scholar 

  108. Zhou, Q. et al. Safety profile of rapamycin perfluorocarbon nanoparticles for preventing cisplatin-induced kidney injury. Nanomaterials 12, 336 (2022).

    Article  CAS  Google Scholar 

  109. Wei, L. et al. AMP-activated protein kinase regulates autophagic protection against cisplatin-induced tissue injury in the kidney. Genet. Mol. Res. 14, 12006–12015 (2015).

    Article  CAS  Google Scholar 

  110. Li, J. et al. Rictor/mTORC2 protects against cisplatin-induced tubular cell death and acute kidney injury. Kidney Int. 86, 86–102 (2014).

    Article  CAS  Google Scholar 

  111. Kimura, A. et al. Interferon-gamma is protective in cisplatin-induced renal injury by enhancing autophagic flux. Kidney Int. 82, 1093–1104 (2012).

    Article  CAS  Google Scholar 

  112. Shen, Q. et al. TLR2 protects cisplatin-induced acute kidney injury associated with autophagy via PI3K/Akt signaling pathway. J. Cell Biochem. 120, 4366–4374 (2019).

    Article  CAS  Google Scholar 

  113. Zhao, C. et al. Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function. Oncotarget 8, 20988–21000 (2017).

    Article  Google Scholar 

  114. Lynch, M. R. et al. TFEB-driven lysosomal biogenesis is pivotal for PGC1alpha-dependent renal stress resistance. JCI Insight 5, e126749 (2020).

    Article  Google Scholar 

  115. Fu, Y. et al. Persistent activation of autophagy after cisplatin nephrotoxicity promotes renal fibrosis and chronic kidney disease. Front. Pharmacol. 13, 918732 (2022).

    Article  CAS  Google Scholar 

  116. Sears, S. M. et al. Pharmacologic inhibitors of autophagy have opposite effects in acute and chronic cisplatin-induced kidney injury. Am. J. Physiol. Renal Physiol. https://doi.org/10.1152/ajprenal.00097.2022 (2022).

    Article  Google Scholar 

  117. Shi, M. et al. In vivo evidence for therapeutic applications of beclin 1 to promote recovery and inhibit fibrosis after acute kidney injury. Kidney Int. 101, 63–78 (2022).

    Article  CAS  Google Scholar 

  118. Minami, S. & Nakamura, S. Therapeutic potential of beclin1 for transition from AKI to CKD: autophagy-dependent and autophagy-independent functions. Kidney Int. 101, 13–15 (2022).

    Article  CAS  Google Scholar 

  119. Baisantry, A. et al. Autophagy induces prosenescent changes in proximal tubular S3 segments. J. Am. Soc. Nephrol. 27, 1609–1616 (2016).

    Article  CAS  Google Scholar 

  120. Livingston, M. J. et al. Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis. Autophagy https://doi.org/10.1080/15548627.2022.2072054 (2022).

    Article  Google Scholar 

  121. Li, L., Wang, Z. V., Hill, J. A. & Lin, F. New autophagy reporter mice reveal dynamics of proximal tubular autophagy. J. Am. Soc. Nephrol. 25, 305–315 (2014).

    Article  CAS  Google Scholar 

  122. Hu, X. et al. FGF2 is produced by renal tubular cells to act as a paracrine factor in maladaptive kidney repair after cisplatin nephrotoxicity. Lab Invest. (2022).

  123. Panagopoulos, A. & Altmeyer, M. The hammer and the dance of cell cycle control. Trends Biochem. Sci. 46, 301–314 (2021).

    Article  CAS  Google Scholar 

  124. Megyesi, J., Safirstein, R. L. & Price, P. M. Induction of p21WAF1/CIP1/SDI1 in kidney tubule cells affects the course of cisplatin-induced acute renal failure. J. Clin. Invest. 101, 777–782 (1998).

    Article  CAS  Google Scholar 

  125. Price, P. M., Safirstein, R. L. & Megyesi, J. Protection of renal cells from cisplatin toxicity by cell cycle inhibitors. Am. J. Physiol. Renal Physiol. 286, F378–F384 (2004).

    Article  CAS  Google Scholar 

  126. Yu, F., Megyesi, J., Safirstein, R. L. & Price, P. M. Identification of the functional domain of p21(WAF1/CIP1) that protects cells from cisplatin cytotoxicity. Am. J. Physiol. Renal Physiol. 289, F514–F520 (2005).

    Article  CAS  Google Scholar 

  127. Price, P. M. et al. Dependence of cisplatin-induced cell death in vitro and in vivo on cyclin-dependent kinase 2. J. Am. Soc. Nephrol. 17, 2434–2442 (2006).

    Article  CAS  Google Scholar 

  128. Yu, F., Megyesi, J., Safirstein, R. L. & Price, P. M. Involvement of the CDK2-E2F1 pathway in cisplatin cytotoxicity in vitro and in vivo. Am. J. Physiol. Renal Physiol. 293, F52–F59 (2007).

    Article  CAS  Google Scholar 

  129. Hodeify, R., Tarcsafalvi, A., Megyesi, J., Safirstein, R. L. & Price, P. M. Cdk2-dependent phosphorylation of p21 regulates the role of Cdk2 in cisplatin cytotoxicity. Am. J. Physiol. Renal Physiol. 300, F1171–F1179 (2011).

    Article  CAS  Google Scholar 

  130. Miyaji, T., Kato, A., Yasuda, H., Fujigaki, Y. & Hishida, A. Role of the increase in p21 in cisplatin-induced acute renal failure in rats. J. Am. Soc. Nephrol. 12, 900–908 (2001).

    Article  CAS  Google Scholar 

  131. Megyesi, J., Andrade, L., Vieira, J. M. Jr, Safirstein, R. L. & Price, P. M. Coordination of the cell cycle is an important determinant of the syndrome of acute renal failure. Am. J. Physiol. Renal Physiol. 283, F810–F816 (2002).

    Article  Google Scholar 

  132. DiRocco, D. P. et al. CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury. Am. J. Physiol. Renal Physiol. 306, F379–F388 (2014).

    Article  CAS  Google Scholar 

  133. Pabla, N. et al. Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions. Proc. Natl Acad. Sci. USA 112, 5231–5236 (2015).

    Article  CAS  Google Scholar 

  134. Kim, J. Y. et al. Ribociclib mitigates cisplatin-associated kidney injury through retinoblastoma-1 dependent mechanisms. Biochem. Pharmacol. 177, 113939 (2020).

    Article  CAS  Google Scholar 

  135. Jin, H. et al. Epithelial innate immunity mediates tubular cell senescence after kidney injury. JCI Insight 4, e125490 (2019).

    Article  Google Scholar 

  136. Li, C. et al. N-acetylcysteine ameliorates cisplatin-induced renal senescence and renal interstitial fibrosis through sirtuin1 activation and p53 deacetylation. Free Radic. Biol. Med. 130, 512–527 (2019).

    Article  CAS  Google Scholar 

  137. Hickson, L. J. et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine 47, 446–456 (2019).

    Article  Google Scholar 

  138. Duan, Z., Cai, G., Li, J. & Chen, X. Cisplatin-induced renal toxicity in elderly people. Ther. Adv. Med. Oncol. 12, 1758835920923430 (2020).

    Article  Google Scholar 

  139. Guan, Y. et al. Nicotinamide mononucleotide, an NAD+ precursor, rescues age-associated susceptibility to AKI in a sirtuin 1-dependent manner. J. Am. Soc. Nephrol. 28, 2337–2352 (2017).

    Article  CAS  Google Scholar 

  140. Wei, M. C. et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001).

    Article  CAS  Google Scholar 

  141. Jiang, M., Wang, C. Y., Huang, S., Yang, T. & Dong, Z. Cisplatin-induced apoptosis in p53-deficient renal cells via the intrinsic mitochondrial pathway. Am. J. Physiol. Renal Physiol. 296, F983–F993 (2009).

    Article  CAS  Google Scholar 

  142. Wei, Q., Dong, G., Franklin, J. & Dong, Z. The pathological role of Bax in cisplatin nephrotoxicity. Kidney Int. 72, 53–62 (2007).

    Article  Google Scholar 

  143. Mihara, M. et al. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 11, 577–590 (2003).

    Article  CAS  Google Scholar 

  144. Nakano, K. & Vousden, K. H. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell. 7, 683–694 (2001).

    Article  CAS  Google Scholar 

  145. Wei, Q. et al. Activation and involvement of p53 in cisplatin-induced nephrotoxicity. Am. J. Physiol. Renal Physiol. 293, F1282–F1291 (2007).

    Article  CAS  Google Scholar 

  146. Zhang, D. et al. Tubular p53 regulates multiple genes to mediate AKI. J. Am. Soc. Nephrol. 25, 2278–2289 (2014).

    Article  CAS  Google Scholar 

  147. Tsuruya, K. et al. Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Kidney Int. 63, 72–82 (2003).

    Article  CAS  Google Scholar 

  148. Linkermann, A. et al. Renal tubular Fas ligand mediates fratricide in cisplatin-induced acute kidney failure. Kidney Int. 79, 169–178 (2011).

    Article  CAS  Google Scholar 

  149. Ramesh, G. & Reeves, W. B. TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure. Am. J. Physiol. Renal Physiol. 285, F610–F618 (2003).

    Article  CAS  Google Scholar 

  150. Iurlaro, R. & Munoz-Pinedo, C. Cell death induced by endoplasmic reticulum stress. FEBS J. 283, 2640–2652 (2016).

    Article  CAS  Google Scholar 

  151. Li, F. et al. Compound C protects against cisplatin-induced nephrotoxicity through pleiotropic effects. Front. Physiol. 11, 614244 (2020).

    Article  Google Scholar 

  152. Choi, M. E., Price, D. R., Ryter, S. W. & Choi, A. M. K. Necroptosis: a crucial pathogenic mediator of human disease. JCI Insight 4, e128834 (2019).

    Article  Google Scholar 

  153. Xu, Y. et al. A role for tubular necroptosis in cisplatin-induced AKI. J. Am. Soc. Nephrol. 26, 2647–2658 (2015).

    Article  CAS  Google Scholar 

  154. Ning, Y. et al. Necrostatin-1 attenuates cisplatin-induced nephrotoxicity through suppression of apoptosis and oxidative stress and retains Klotho expression. Front. Pharmacol. 9, 384 (2018).

    Article  Google Scholar 

  155. Wang, J. N. et al. RIPK1 inhibitor Cpd-71 attenuates renal dysfunction in cisplatin-treated mice via attenuating necroptosis, inflammation and oxidative stress. Clin. Sci. 133, 1609–1627 (2019).

    Article  CAS  Google Scholar 

  156. Guo, X. et al. Kidney-targeted renalase agonist prevents cisplatin-induced chronic kidney disease by inhibiting regulated necrosis and inflammation. J. Am. Soc. Nephrol. 33, 342–356 (2022).

    Article  CAS  Google Scholar 

  157. Li, Y. et al. Activation of GSDMD contributes to acute kidney injury induced by cisplatin. Am. J. Physiol. Renal Physiol. 318, F96–F106 (2020).

    Article  CAS  Google Scholar 

  158. Miao, N. et al. The cleavage of gasdermin D by caspase-11 promotes tubular epithelial cell pyroptosis and urinary IL-18 excretion in acute kidney injury. Kidney Int. 96, 1105–1120 (2019).

    Article  CAS  Google Scholar 

  159. Xia, W. et al. Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation. Cell Death Dis. 12, 139 (2021).

    Article  CAS  Google Scholar 

  160. Shen, X., Wang, H., Weng, C., Jiang, H. & Chen, J. Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity. Cell Death Dis. 12, 186 (2021).

    Article  CAS  Google Scholar 

  161. Jiang, X., Stockwell, B. R. & Conrad, M. Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266–282 (2021).

    Article  Google Scholar 

  162. Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16, 1180–1191 (2014).

    Article  CAS  Google Scholar 

  163. Deng, F., Sharma, I., Dai, Y., Yang, M. & Kanwar, Y. S. Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule. J. Clin. Invest. 129, 5033–5049 (2019).

    Article  CAS  Google Scholar 

  164. Mishima, E. et al. Drugs repurposed as antiferroptosis agents suppress organ damage, including AKI, by functioning as lipid peroxyl radical scavengers. J. Am. Soc. Nephrol. 31, 280–296 (2020).

    Article  CAS  Google Scholar 

  165. Ikeda, Y. et al. Role of ferroptosis in cisplatin-induced acute nephrotoxicity in mice. J. Trace Elem. Med. Biol. 67, 126798 (2021).

    Article  CAS  Google Scholar 

  166. Hu, Z. et al. VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis. Cell Death Dis. 11, 73 (2020).

    Article  CAS  Google Scholar 

  167. Zazuli, Z. et al. Association between genetic variants and cisplatin-induced nephrotoxicity: a genome-wide approach and validation study. J. Pers. Med. 11, 1233 (2021).

    Article  Google Scholar 

  168. Andrade-Silva, M. et al. TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury. Clin. Sci. 132, 1725–1739 (2018).

    Article  CAS  Google Scholar 

  169. Zhang, B., Ramesh, G., Uematsu, S., Akira, S. & Reeves, W. B. TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. J. Am. Soc. Nephrol. 19, 923–932 (2008).

    Article  CAS  Google Scholar 

  170. Alikhan, M. A. et al. Endogenous toll-like receptor 9 regulates AKI by promoting regulatory T cell recruitment. J. Am. Soc. Nephrol. 27, 706–714 (2016).

    Article  CAS  Google Scholar 

  171. Maekawa, H. et al. Mitochondrial damage causes inflammation via cGAS-STING signaling in acute kidney injury. Cell Rep. 29, 1261–1273 e1266 (2019).

    Article  CAS  Google Scholar 

  172. Gong, W. et al. The novel STING antagonist H151 ameliorates cisplatin-induced acute kidney injury and mitochondrial dysfunction. Am. J. Physiol. Renal Physiol. 320, F608–F616 (2021).

    Article  CAS  Google Scholar 

  173. Kim, H. J. et al. NLRP3 inflammasome knockout mice are protected against ischemic but not cisplatin-induced acute kidney injury. J. Pharmacol. Exp. Ther. 346, 465–472 (2013).

    Article  CAS  Google Scholar 

  174. Li, S. et al. NLRP3 inflammasome inhibition attenuates cisplatin-induced renal fibrosis by decreasing oxidative stress and inflammation. Exp. Cell Res. 383, 111488 (2019).

    Article  CAS  Google Scholar 

  175. Lv, L. L. et al. The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation. Kidney Int. 91, 587–602 (2017).

    Article  CAS  Google Scholar 

  176. Holbrook, J., Lara-Reyna, S., Jarosz-Griffiths, H. & McDermott, M. Tumour necrosis factor signalling in health and disease. F1000Res. https://doi.org/10.12688/f1000research.17023.1 (2019).

    Article  Google Scholar 

  177. Dong, Z. & Atherton, S. S. Tumor necrosis factor-alpha in cisplatin nephrotoxicity: a homebred foe? Kidney Int. 72, 5–7 (2007).

    Article  CAS  Google Scholar 

  178. Ramesh, G. & Reeves, W. B. TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J. Clin. Invest. 110, 835–842 (2002).

    Article  CAS  Google Scholar 

  179. Zhang, J. et al. Competing actions of type 1 angiotensin II receptors expressed on T lymphocytes and kidney epithelium during cisplatin-induced AKI. J. Am. Soc. Nephrol. 27, 2257–2264 (2016).

    Article  CAS  Google Scholar 

  180. Liu, M. et al. A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity. J. Am. Soc. Nephrol. 17, 765–774 (2006).

    Article  CAS  Google Scholar 

  181. Lee, H. et al. CD4+CD25+ regulatory T cells attenuate cisplatin-induced nephrotoxicity in mice. Kidney Int. 78, 1100–1109 (2010).

    Article  CAS  Google Scholar 

  182. Faubel, S. et al. Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1β, IL-18, IL-6, and neutrophil infiltration in the kidney. J. Pharmacol. Exp. Ther. 322, 8–15 (2007).

    Article  CAS  Google Scholar 

  183. Privratsky, J. R. et al. Interleukin 1 receptor (IL-1R1) activation exacerbates toxin-induced acute kidney injury. Am. J. Physiol. Renal Physiol. 315, F682–F691 (2018).

    Article  CAS  Google Scholar 

  184. Nozaki, Y. et al. Signaling through the interleukin-18 receptor α attenuates inflammation in cisplatin-induced acute kidney injury. Kidney Int. 82, 892–902 (2012).

    Article  CAS  Google Scholar 

  185. Mitazaki, S. et al. Interleukin-6 plays a protective role in development of cisplatin-induced acute renal failure through upregulation of anti-oxidative stress factors. Life Sci. 88, 1142–1148 (2011).

    Article  CAS  Google Scholar 

  186. Mitazaki, S., Kato, N., Suto, M., Hiraiwa, K. & Abe, S. Interleukin-6 deficiency accelerates cisplatin-induced acute renal failure but not systemic injury. Toxicology 265, 115–121 (2009).

    Article  CAS  Google Scholar 

  187. Tadagavadi, R. K. & Reeves, W. B. Endogenous IL-10 attenuates cisplatin nephrotoxicity: role of dendritic cells. J. Immunol. 185, 4904–4911 (2010).

    Article  CAS  Google Scholar 

  188. Wang, W. W. et al. IL-10 from dendritic cells but not from T regulatory cells protects against cisplatin-induced nephrotoxicity. PLoS One 15, e0238816 (2020).

    Article  CAS  Google Scholar 

  189. Deng, J. et al. Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney Int. 60, 2118–2128 (2001).

    Article  CAS  Google Scholar 

  190. Ma, Z. et al. Single-nucleus transcriptional profiling of chronic kidney disease after cisplatin nephrotoxicity. Am. J. Pathol. 192, 613–628 (2022).

    Article  CAS  Google Scholar 

  191. Schett, G. & Neurath, M. F. Resolution of chronic inflammatory disease: universal and tissue-specific concepts. Nat. Commun. 9, 3261 (2018).

    Article  Google Scholar 

  192. Guo, C. et al. DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8. Kidney Int. 92, 1194–1205 (2017).

    Article  CAS  Google Scholar 

  193. Bao, Y. et al. DNA demethylase Tet2 suppresses cisplatin-induced acute kidney injury. Cell Death Discov. 7, 167 (2021).

    Article  CAS  Google Scholar 

  194. Yu, Z. et al. Vitamin C deficiency causes cell type-specific epigenetic reprogramming and acute tubular necrosis in a mouse model. J. Am. Soc. Nephrol. 33, 531–546 (2022).

    Article  CAS  Google Scholar 

  195. Jiang, X. et al. The role of m6A modification in the biological functions and diseases. Signal. Transduct. Target. Ther. 6, 74 (2021).

    Article  CAS  Google Scholar 

  196. Li, C. M., Li, M., Zhao, W. B., Ye, Z. C. & Peng, H. Alteration of N6-methyladenosine RNA profiles in cisplatin-induced acute kidney injury in mice. Front. Mol. Biosci. 8, 654465 (2021).

    Article  CAS  Google Scholar 

  197. Shen, J. et al. Integrated analysis of m6A methylome in cisplatin-induced acute kidney injury and berberine alleviation in mouse. Front. Genet. 11, 584460 (2020).

    Article  CAS  Google Scholar 

  198. Zhou, P., Wu, M., Ye, C., Xu, Q. & Wang, L. Meclofenamic acid promotes cisplatin-induced acute kidney injury by inhibiting fat mass and obesity-associated protein-mediated m6A abrogation in RNA. J. Biol. Chem. 294, 16908–16917 (2019).

    Article  CAS  Google Scholar 

  199. Wang, J. N. et al. Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms. Sci. Transl. Med. 14, eabk2709 (2022).

    Article  CAS  Google Scholar 

  200. Graff, J. & Tsai, L. H. Histone acetylation: molecular mnemonics on the chromatin. Nat. Rev. Neurosci. 14, 97–111 (2013).

    Article  Google Scholar 

  201. Kim, J. Y., Jo, J., Leem, J. & Park, K. K. Inhibition of p300 by garcinol protects against cisplatin-induced acute kidney injury through suppression of oxidative stress, inflammation, and tubular cell death in mice. Antioxidants 9, 1271 (2020).

    Article  CAS  Google Scholar 

  202. Sun, L., Liu, J., Yuan, Y., Zhang, X. & Dong, Z. Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity. Am. J. Physiol. Renal Physiol. 315, F469–F478 (2018).

    Article  CAS  Google Scholar 

  203. Dong, G., Luo, J., Kumar, V. & Dong, Z. Inhibitors of histone deacetylases suppress cisplatin-induced p53 activation and apoptosis in renal tubular cells. Am. J. Physiol. Renal Physiol. 298, F293–F300 (2010).

    Article  CAS  Google Scholar 

  204. Zhu, H. et al. PSTPIP2 inhibits cisplatin-induced acute kidney injury by suppressing apoptosis of renal tubular epithelial cells. Cell Death Dis. 11, 1057 (2020).

    Article  CAS  Google Scholar 

  205. Ranganathan, P. et al. Histone deacetylase-mediated silencing of AMWAP expression contributes to cisplatin nephrotoxicity. Kidney Int. 89, 317–326 (2016).

    Article  CAS  Google Scholar 

  206. Mikami, D. et al. β-Hydroxybutyrate, a ketone body, reduces the cytotoxic effect of cisplatin via activation of HDAC5 in human renal cortical epithelial cells. Life Sci. 222, 125–132 (2019).

    Article  CAS  Google Scholar 

  207. Tang, J. et al. Blockade of histone deacetylase 6 protects against cisplatin-induced acute kidney injury. Clin. Sci. 132, 339–359 (2018).

    Article  CAS  Google Scholar 

  208. Kim, D. H. et al. SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53. Am. J. Physiol. Renal Physiol. 301, F427–F435 (2011).

    Article  CAS  Google Scholar 

  209. Kim, J. Y. et al. Pharmacological activation of Sirt1 ameliorates cisplatin-induced acute kidney injury by suppressing apoptosis, oxidative stress, and inflammation in mice. Antioxidants 8, 322 (2019).

    Article  CAS  Google Scholar 

  210. Li, M. et al. Sirt3 modulates fatty acid oxidation and attenuates cisplatin-induced AKI in mice. J. Cell Mol. Med. 24, 5109–5121 (2020).

    Article  CAS  Google Scholar 

  211. Li, Z. et al. Overexpressed SIRT6 attenuates cisplatin-induced acute kidney injury by inhibiting ERK1/2 signaling. Kidney Int. 93, 881–892 (2018).

    Article  CAS  Google Scholar 

  212. Miyasato, Y. et al. Sirtuin 7 deficiency ameliorates cisplatin-induced acute kidney injury through regulation of the inflammatory response. Sci. Rep. 8, 5927 (2018).

    Article  Google Scholar 

  213. Jung, Y. J., Park, W., Kang, K. P. & Kim, W. SIRT2 is involved in cisplatin-induced acute kidney injury through regulation of mitogen-activated protein kinase phosphatase-1. Nephrol. Dial. Transpl. 35, 1145–1156 (2020).

    Article  CAS  Google Scholar 

  214. O’Brien, J., Hayder, H., Zayed, Y. & Peng, C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. 9, 402 (2018).

    Article  Google Scholar 

  215. de Godoy Torso, N. et al. Dysregulated microRNAs as biomarkers or therapeutic targets in cisplatin-induced nephrotoxicity: a systematic review. Int. J. Mol. Sci. 22, 12765 (2021).

    Article  Google Scholar 

  216. Bhatt, K. et al. MicroRNA-34a is induced via p53 during cisplatin nephrotoxicity and contributes to cell survival. Mol. Med. 16, 409–416 (2010).

    Article  CAS  Google Scholar 

  217. Guo, Y. et al. MicroRNA-709 mediates acute tubular injury through effects on mitochondrial function. J. Am. Soc. Nephrol. 29, 449–461 (2018).

    Article  CAS  Google Scholar 

  218. Hao, J. et al. MicroRNA-375 is induced in cisplatin nephrotoxicity to repress hepatocyte nuclear factor 1-β. J. Biol. Chem. 292, 4571–4582 (2017).

    Article  CAS  Google Scholar 

  219. Lee, C. G. et al. Discovery of an integrative network of microRNAs and transcriptomics changes for acute kidney injury. Kidney Int. 86, 943–953 (2014).

    Article  CAS  Google Scholar 

  220. Pellegrini, K. L. et al. MicroRNA-155 deficient mice experience heightened kidney toxicity when dosed with cisplatin. Toxicol. Sci. 141, 484–492 (2014).

    Article  CAS  Google Scholar 

  221. Liao, W. et al. MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism. Exp. Cell Res. 360, 292–302 (2017).

    Article  CAS  Google Scholar 

  222. Du, B. et al. MiR-30c regulates cisplatin-induced apoptosis of renal tubular epithelial cells by targeting Bnip3L and Hspa5. Cell Death Dis. 8, e2987 (2017).

    Article  CAS  Google Scholar 

  223. Statello, L., Guo, C. J., Chen, L. L. & Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 22, 96–118 (2021).

    Article  CAS  Google Scholar 

  224. Zhang, Y. et al. Long non-coding RNA LRNA9884 promotes acute kidney injury via regulating NF-kB-mediated transcriptional activation of MIF. Front. Physiol. 11, 590027 (2020).

    Article  Google Scholar 

  225. Chang, S. et al. LncRNA OIP5-AS1 reduces renal epithelial cell apoptosis in cisplatin-induced AKI by regulating the miR-144-5p/PKM2 axis. Biomed. J. https://doi.org/10.1016/j.bj.2021.07.005 (2021).

    Article  Google Scholar 

  226. Li, J., Fan, X., Wang, Q., Gong, Y. & Guo, L. Long noncoding RNA PRNCR1 reduces renal epithelial cell apoptosis in cisplatin-induced AKI by regulating miR-182-5p/EZH1. Kidney Blood Press. Res. 46, 162–172 (2021).

    Article  CAS  Google Scholar 

  227. Zhou, X. et al. Novel lncRNA XLOC_032768 alleviates cisplatin-induced apoptosis and inflammatory response of renal tubular epithelial cells through TNF-α. Int. Immunopharmacol. 83, 106472 (2020).

    Article  CAS  Google Scholar 

  228. Greene, J. et al. Circular RNAs: biogenesis, function and role in human diseases. Front. Mol. Biosci. 4, 38 (2017).

    Article  Google Scholar 

  229. Cao, Y. et al. Transcriptome sequencing of circular RNA reveals a novel circular RNA-has_circ_0114427 in the regulation of inflammation in acute kidney injury. Clin. Sci. 134, 139–154 (2020).

    Article  CAS  Google Scholar 

  230. Li, C. M. et al. Circular RNA expression profiles in cisplatin-induced acute kidney injury in mice. Epigenomics 11, 1191–1207 (2019).

    Article  CAS  Google Scholar 

  231. Wu, L. et al. Bone marrow mesenchymal stem cells ameliorate cisplatin-induced renal fibrosis via miR-146a-5p/Tfdp2 axis in renal tubular epithelial cells. Front. Immunol. 11, 623693 (2020).

    Article  CAS  Google Scholar 

  232. Zarjou, A. et al. Paracrine effects of mesenchymal stem cells in cisplatin-induced renal injury require heme oxygenase-1. Am. J. Physiol. Renal Physiol. 300, F254–F262 (2011).

    Article  CAS  Google Scholar 

  233. Zhang, R. et al. Resveratrol improves human umbilical cord-derived mesenchymal stem cells repair for cisplatin-induced acute kidney injury. Cell Death Dis. 9, 965 (2018).

    Article  Google Scholar 

  234. Huang, X., Ma, Y., Li, Y., Han, F. & Lin, W. Targeted drug delivery systems for kidney diseases. Front. Bioeng. Biotechnol. 9, 683247 (2021).

    Article  Google Scholar 

  235. Weng, Q. et al. Catalytic activity tunable ceria nanoparticles prevent chemotherapy-induced acute kidney injury without interference with chemotherapeutics. Nat. Commun. 12, 1436 (2021).

    Article  CAS  Google Scholar 

  236. Moreno-Gordaliza, E., Marazuela, M. D., Pastor, O., Lazaro, A. & Gomez-Gomez, M. M. Lipidomics reveals cisplatin-induced renal lipid alterations during acute kidney injury and their attenuation by cilastatin. Int. J. Mol. Sci. 22, 12521 (2021).

    Article  CAS  Google Scholar 

  237. Spath, M. R. et al. The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury. Kidney Int. 95, 333–349 (2019).

    Article  Google Scholar 

  238. Wu, R. et al. Comprehensive molecular and cellular characterization of acute kidney injury progression to renal fibrosis. Front. Immunol. 12, 699192 (2021).

    Article  CAS  Google Scholar 

  239. Joo, M. S., Lee, C. G., Koo, J. H. & Kim, S. G. miR-125b transcriptionally increased by Nrf2 inhibits AhR repressor, which protects kidney from cisplatin-induced injury. Cell Death Dis. 4, e899 (2013).

    Article  CAS  Google Scholar 

  240. Liu, H. & Baliga, R. Cytochrome P450 2E1 null mice provide novel protection against cisplatin-induced nephrotoxicity and apoptosis. Kidney Int. 63, 1687–1696 (2003).

    Article  CAS  Google Scholar 

  241. Sahu, B. D., Mahesh Kumar, J. & Sistla, R. Baicalein, a bioflavonoid, prevents cisplatin-induced acute kidney injury by up-regulating antioxidant defenses and down-regulating the MAPKs and NF-κB pathways. PLoS One 10, e0134139 (2015).

    Article  Google Scholar 

Download references

Acknowledgements

The authors’ work was supported in part by grants from the National Natural Science Foundation of China (81870474), the National Institutes of Health (DK058831, DK087843) and the US Department of Veterans Affairs (BX000319). Z.D. is a recipient of the Senior Research Career Scientist award from the US Department of Veterans Affairs.

Author information

Authors and Affiliations

  1. Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

    Chengyuan Tang & Zheng Dong

  2. Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA

    Man J. Livingston & Zheng Dong

  3. Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Robert Safirstein

Authors
  1. Chengyuan Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Man J. Livingston
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert Safirstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zheng Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.T. and Z.D. researched data for the article and wrote the text. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Zheng Dong.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Nephrology thanks W. Brian Reeves, Aihua Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Mitophagy

A cellular process that selectively removes damaged or obsolete mitochondria via the autophagy–lysosome pathway.

Ferritinophagy

A selective form of autophagy in which nuclear receptor coactivator 4 selectively binds to and delivers iron-laden ferritin to autophagosomes, leading to ferritin degradation in lysosomes and the release of free irons into the cytosol.

Pattern recognition receptors

Receptors that recognize molecules from pathogens or released by damaged cells and subsequently trigger intracellular signalling cascades to induce transcriptional expression of inflammatory mediators that coordinate the elimination of pathogens and infected cells.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tang, C., Livingston, M.J., Safirstein, R. et al. Cisplatin nephrotoxicity: new insights and therapeutic implications. Nat Rev Nephrol 19, 53–72 (2023). https://doi.org/10.1038/s41581-022-00631-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-022-00631-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing