ResearchIn-Press PreviewNephrology
Open Access | 10.1172/jci.insight.166643
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
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Li, S.
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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
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Livingston, M.
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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
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Hu, X.
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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
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Ding, H.
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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
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Dong, Z.
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Published March 14, 2023 - More info
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.