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
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Cisplatin is nephrotoxin that can cause both acute kidney injury and chronic kidney disease.
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Accumulation of cisplatin in renal tubular cells induces various intracellular stresses, including DNA damage, mitochondrial pathology, oxidative stress and endoplasmic reticulum stress.
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Multiple stress responses, including autophagy, cell-cycle arrest, senescence, apoptosis, programmed necrosis and inflammation, have important roles in the pathogenesis of cisplatin nephrotoxicity.
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Epigenetic mechanisms, including histone acetylation, DNA and messenger RNA methylation and gene regulation by non-coding RNAs also contribute to cisplatin nephrotoxicity.
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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.
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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.
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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.
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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.
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Glossary
- Mitophagy
-
A cellular process that selectively removes damaged or obsolete mitochondria via the autophagy–lysosome pathway.
- Ferritinophagy
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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.
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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
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DOI: https://doi.org/10.1038/s41581-022-00631-7