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ResearchIn-Press PreviewNephrology Open Access | 10.1172/jci.insight.166643

Tubular cell senescence promotes maladaptive kidney repair and chronic kidney disease after cisplatin nephrotoxicity

Siyao Li,1 Man J. Livingston,2 Zhengwei Ma,2 Xiaoru Hu,1 Lu Wen,1 Han-Fei Ding,3 Daohong Zhou,4 and Zheng Dong1

1Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China

2Department of Cellular Biology and Anatomy, Augusta University, Augusta, United States of America

3Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, United States of America

4Department of Biochemistry & Structural Biology, University of Texas Health Science Center, San Antonio, United States of America

Find articles by Li, S. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China

2Department of Cellular Biology and Anatomy, Augusta University, Augusta, United States of America

3Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, United States of America

4Department of Biochemistry & Structural Biology, University of Texas Health Science Center, San Antonio, United States of America

Find articles by Livingston, M. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China

2Department of Cellular Biology and Anatomy, Augusta University, Augusta, United States of America

3Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, United States of America

4Department of Biochemistry & Structural Biology, University of Texas Health Science Center, San Antonio, United States of America

Find articles by Ma, Z. in: JCI | PubMed | Google Scholar

1Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China

2Department of Cellular Biology and Anatomy, Augusta University, Augusta, United States of America

3Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, United States of America

4Department of Biochemistry & Structural Biology, University of Texas Health Science Center, San Antonio, United States of America

Find articles by Hu, X. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China

2Department of Cellular Biology and Anatomy, Augusta University, Augusta, United States of America

3Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, United States of America

4Department of Biochemistry & Structural Biology, University of Texas Health Science Center, San Antonio, United States of America

Find articles by Wen, L. in: JCI | PubMed | Google Scholar

1Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China

2Department of Cellular Biology and Anatomy, Augusta University, Augusta, United States of America

3Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, United States of America

4Department of Biochemistry & Structural Biology, University of Texas Health Science Center, San Antonio, United States of America

Find articles by Ding, H. in: JCI | PubMed | Google Scholar |

1Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China

2Department of Cellular Biology and Anatomy, Augusta University, Augusta, United States of America

3Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, United States of America

4Department of Biochemistry & Structural Biology, University of Texas Health Science Center, San Antonio, United States of America

Find articles by Zhou, D. in: JCI | PubMed | Google Scholar

1Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China

2Department of Cellular Biology and Anatomy, Augusta University, Augusta, United States of America

3Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, United States of America

4Department of Biochemistry & Structural Biology, University of Texas Health Science Center, San Antonio, United States of America

Find articles by Dong, Z. in: JCI | PubMed | Google Scholar |

Published March 14, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.166643.
Copyright © 2023, Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 14, 2023 - Version history
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Abstract

Cisplatin is a widely used chemotherapy drug but it induces both acute and chronic kidney diseases (CKD) in cancer patients. The pathogenesis of cisplatin-induced CKD is unclear and effective renoprotective approaches are not available. Here, we report that repeated low-dose cisplatin (RLDC) treatment of C57BL/6 mice induced chronic cellular senescence in kidney tubules, accompanied with tubular degeneration and pro-fibrotic phenotype transformation that culminated in maladaptive repair and renal fibrosis. Suppression of tubular senescence by senolytic drugs ABT-263 and Fisetin attenuated renal fibrosis and improved tubular repair as indicated by restoration of tubular regeneration and renal function. In vitro, RLDC also induced senescence in mouse proximal tubular BUMPT cells. ABT-263 eliminated senescent BUMPT cells following RLDC treatment, reversed the pro-fibrotic phenotype of the cells and increased their clonogenic activity. Moreover, ABT-263 alleviated the paracrine effect of RLDC-treated BUMPT cells on fibroblasts for fibrosis. Consistently, knockdown of p16 suppressed post-RLDC senescence and fibrotic changes in BUMPT cells, and alleviated their paracrine effects on renal fibroblast proliferation. These results indicate that persistent induction of tubular senescence plays an important role in promoting cisplatin-induced CKD. Targeting senescent tubular cells may be efficient to improve kidney repair for the prevention and treatment of cisplatin-induced CKD.

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