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A comparative review of murine models of repeated low-dose cisplatin-induced chronic kidney disease

Lab Animal volume 54, pages 42–49 (2025)Cite this article

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Abstract

This Review evaluates various mouse and rat models of chronic kidney disease (CKD) that result from repeated low-dose cisplatin (RLDC) treatment while also discussing ethical considerations on the topic. Cisplatin can cause nephrotoxicity, and high doses of cisplatin can cause acute kidney injury. The RLDC regimen has been used in the treatment of solid organ cancers and has shown efficacy in reducing the occurrence of acute kidney injury in patients. However, prolonged treatments may lead to CKD. Mouse and rat models that effectively replicate the pathological features of CKD are invaluable for studying the mechanisms of the disease and exploring potential therapeutic interventions. Whereas administration of a single higher dose in some RLDC models may lead to higher mortality rates, a single lower dose may not replicate the fibrotic characteristics of CKD. Here we gathered information on mouse and rat models of RLDC-induced CKD and analyzed the impact of different variables, such as animal age, cisplatin dosage and administration frequency, on success rates, mortality rate and weight loss. Among the different models, weekly intraperitoneal administration of 8 mg/kg or 9 mg/kg of cisplatin for a total of 4 weeks in 12-week-old male C57BL/6 mice showed the most similar clinical characteristics of CKD while adhering to ethical requirements. In this Review, we suggest the best timings for both drug intervention and observation based on the biological traits of the model. Furthermore, given the limited research available on RLDC-induced CKD rat models, it is urgent to focus on developing RLDC methods that can induce detailed characteristics of CKD in rats.

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References

  1. Tang, C., Livingston, M. J., Safirstein, R. & Dong, Z. Cisplatin nephrotoxicity: new insights and therapeutic implications. Nat. Rev. Nephrol. 19, 53–72 (2023).

    Article  CAS  PubMed  Google Scholar 

  2. McSweeney, K. R. et al. Mechanisms of cisplatin-induced acute kidney injury: pathological mechanisms, pharmacological interventions, and genetic mitigations. Cancers 13, 1572 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bhat, Z. Y. et al. Understanding the risk factors and long-term consequences of cisplatin-associated acute kidney injury: an observational cohort study. PLoS ONE 10, e0142225 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Menon, N. S. et al. Quality of life in patients with locally advanced head and neck squamous cell carcinoma undergoing concurrent chemoradiation with once-a-week versus once-every-3-weeks cisplatin. Cancer Med 11, 3939–3948 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kiyota, N. et al. Weekly cisplatin plus radiation for postoperative head and neck cancer (jcog1008): a multicenter, noninferiority, phase II/III randomized controlled trial. J. Clin. Oncol. 40, 1980–1990 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Suppadungsuk, S. et al. Preloading magnesium attenuates cisplatin-associated nephrotoxicity: pilot randomized controlled trial (PRAGMATIC study). ESMO Open 7, 100351 (2022).

    Article  CAS  PubMed  Google Scholar 

  7. Mapuskar, K. A. et al. The antioxidant and anti-inflammatory activities of avasopasem manganese in age-associated, cisplatin-induced renal injury. Redox Biol. 70, 103022 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mapuskar, K. A. et al. Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: an exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients. Redox Biol. 60, 102599 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sears, S. M. & Siskind, L. J. Potential therapeutic targets for cisplatin-induced kidney injury: lessons from other models of AKI and fibrosis. J. Am. Soc. Nephrol. 32, 1559–1567 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Qiu, C.-W., Chen, B., Zhu, H.-F., Liang, Y.-L. & Mao, L.-S. Gastrodin alleviates cisplatin nephrotoxicity by inhibiting ferroptosis via the SIRT1/FOXO3A/GPX4 signaling pathway. J. Ethnopharmacol. https://doi.org/10.1016/j.jep.2023.117282 (2024).

  11. Zhang, D. et al. Protein kinase Cδ suppresses autophagy to induce kidney cell apoptosis in cisplatin nephrotoxicity. J. Am. Soc. Nephrol. 28, 1131–1144 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. Shi, M. et al. Cisplatin nephrotoxicity as a model of chronic kidney disease. Lab Invest. 98, 1105–1121 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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  PubMed  PubMed Central  Google Scholar 

  14. Balmer, L. A. et al. Genetic characterization of early renal changes in a novel mouse model of diabetic kidney disease. Kidney Int. 96, 918–926 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. 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  PubMed  Google Scholar 

  16. 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  PubMed  PubMed Central  Google Scholar 

  17. Su, H. et al. Subcellular trafficking of tubular MDM2 implicates in acute kidney injury to chronic kidney disease transition during multiple low-dose cisplatin exposure. FASEB J. 34, 1620–1636 (2020).

    Article  CAS  PubMed  Google Scholar 

  18. 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  PubMed  Google Scholar 

  19. 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  PubMed  PubMed Central  Google Scholar 

  20. Sharp, C. N. & Siskind, L. J. Developing better mouse models to study cisplatin-induced kidney injury. Am. J. Physiol. Renal Physiol. 313, F835–f841 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  21. 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  PubMed  Google Scholar 

  22. Li, S. et al. Tubular cell senescence promotes maladaptive kidney repair and chronic kidney disease after cisplatin nephrotoxicity. JCI Insight 8, e166643 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  23. 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  PubMed  PubMed Central  Google Scholar 

  24. Sears, S. M. et al. Pharmacological inhibitors of autophagy have opposite effects in acute and chronic cisplatin-induced kidney injury. Am. J. Physiol. Renal Physiol. 323, F288–F298 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tsai, Y. S. et al. Lactobacillus rhamnosus GKLC1 ameliorates cisplatin-induced chronic nephrotoxicity by inhibiting cell inflammation and apoptosis. Biomed. Pharmacother. 147, 112701 (2022).

    Article  CAS  PubMed  Google Scholar 

  26. 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  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Garovic, V. D. & August, P. Sex differences and renal protection: keeping in touch with your feminine side. J. Am. Soc. Nephrol. 27, 2921–2924 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Boddu, R. et al. Unique sex- and age-dependent effects in protective pathways in acute kidney injury. Am. J. Physiol. Renal Physiol. 313, F740–f755 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fu, Y. et al. The STAT1/HMGB1/NF-κB pathway in chronic inflammation and kidney injury after cisplatin exposure. Theranostics 13, 2757–2773 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shi, G. et al. RB/T 173-2018. Guidelines of Assessment for Humane Endpoints in Animal Experiment (National Certification and Accreditation Administration, 2018).

  33. Talbot, S. R. et al. Defining body-weight reduction as a humane endpoint: a critical appraisal. Lab. Anim. 54, 99–110 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Morton, D. B. Humane endpoints in animal experimentation for biomedical research: ethical, legal and practical aspects. In Humane Endpoints in Animal Experiments for Biomedical Research (eds Hendriksen, C. F. M. & Morton, D. B.) 5–12 (The Royal Society Medical Press, 1998).

  35. El-Waseif, E. G., Sharawy, M. H. & Suddek, G. M. The modulatory effect of sodium molybdate against cisplatin-induced CKD: role of TGF-β/Smad signaling pathway. Life Sci. 306, 120845 (2022).

    Article  CAS  PubMed  Google Scholar 

  36. Xing, Z., Gong, K., Hu, N. & Chen, Y. The reduction of uromodulin, complement factor H, and their interaction is associated with acute kidney injury to chronic kidney disease transition in a four-time cisplatin-injected rat model. Int. J. Mol. Sci. 24, 6636 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shati, A. A. et al. Comparison of the ameliorative roles of crab chitosan nanoparticles and mesenchymal stem cells against cisplatin-triggered nephrotoxicity. Int. J. Biol. Macromol. 242, 124985 (2023).

    Article  CAS  PubMed  Google Scholar 

  38. Al Za’abi, M. et al. Effects of repeated increasing doses of cisplatin as models of acute kidney injury and chronic kidney disease in rats. Naunyn Schmiedebergs Arch. Pharmacol. 394, 249–259 (2021).

    Article  PubMed  Google Scholar 

  39. Gholami, A. et al. The ameliorating effect of Limosilactobacillus fermentum and its supernatant postbiotic on cisplatin-induced chronic kidney disease in an animal model. BMC Complement. Med. Ther. 23, 243 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The study was supported by grants from the Office of Science and Technology and Talent Work of Luzhou (2024LZXNYDJ082) and Science and Technology Department of Sichuan Province (2022YFS0621).

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Authors and Affiliations

  1. Department of Urology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China

    Hong-Wei Su

  2. Research Center of Combine Traditional Chinese and Western Medicine, Prophylaxis and Treatment of Organ Fibrosis by Integrated Medicine of Luzhou Key Laboratory, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China

    Cai-Wei Qiu

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  1. Hong-Wei Su
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  2. Cai-Wei Qiu
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H.-W.S. analyzed the literature and revised the manuscript. C.-W.Q. supervised the project and wrote the manuscript.

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Correspondence to Cai-Wei Qiu.

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Su, HW., Qiu, CW. A comparative review of murine models of repeated low-dose cisplatin-induced chronic kidney disease. Lab Anim 54, 42–49 (2025). https://doi.org/10.1038/s41684-024-01504-1

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