@article{1babbf19fa984a198591cd049222f0f3,
title = "Cisplatin-Mediated Upregulation of APE2 Binding to MYH9 Provokes Mitochondrial Fragmentation and Acute Kidney Injury",
abstract = "Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI (acute kidney injury, AKI) in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease.",
author = "Yi Hu and Chun Yang and Tania Amorim and Mohsin Maqbool and Jenny Lin and Chen Li and Chuanfeng Fang and Li Xue and Ariel Kwart and Hua Fang and Mei Yin and Janocha, {Allison J.} and Daisuke Tsuchimoto and Yusaku Nakabeppu and Xiaofeng Jiang and Alex Mejia-Garcia and Faiz Anwer and Jack Khouri and Xin Qi and Zheng, {Qing Y.} and Yu, {Jennifer S.} and Shan Yan and Thomas LaFramboise and Anderson, {Kenneth C.} and Herlitz, {Leal C.} and Munshi, {Nikhil C.} and Jianhong Lin and Jianjun Zhao",
note = "Funding Information: The authors thank the Lerner Research Institute proteomic, genomic and imaging cores for their assistance and support. The authors thank Dr. Mark R. Kelley from Indiana University School of Medicine, Drs. Thomas M. McIntyre, Thomas Egelhoff, Donna M. Driscoll, and Serpil C. Erzurum from Cleveland Clinic Lerner Research Institute for valuable discussions. This work was supported by grants (to J. Zhao) from the National Cancer Institute (R00 CA172292), start-up funds and two core utilization pilot grants from the Clinical and Translational Science Collaborative of Cleveland, a V Foundation Scholar Award, an American Society of Hematology (ASH) Bridge Grant, an American Cancer Society Institutional Research Grant Pilot Award, a National Institutes of Health training grant (T32 CA094186, “Training in Computational Genomic Epidemiology of Cancer” to J. Lin), a grant (R01 DC015111/ NIDCD to Q.Y. Zheng) from National Institutes of Health, and a grant (R01HL60917 to Serpil C. Erzurum) from National Institutes of Health, a grant (5UL1TR002548) from the NIH National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health and NIH roadmap for Medical Research. The Orbitrap Elite instrument was purchased with the help of an NIH shared-instrument grant (1S10RR031537-01). Funding Information: The authors thank the Lerner Research Institute proteomic, genomic and imaging cores for their assistance and support. The authors thank Dr. Mark R. Kelley from Indiana University School of Medicine, Drs. Thomas M. McIntyre, Thomas Egelhoff, Donna M. Driscoll, and Serpil C. Erzurum from Cleveland Clinic Lerner Research Institute for valuable discussions. This work was supported by grants (to J. Zhao) from the National Cancer Institute (R00 CA172292), start-up funds and two core utilization pilot grants from the Clinical and Translational Science Collaborative of Cleveland, a V Foundation Scholar Award, an American Society of Hematology Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research Inc.. All rights reserved.",
year = "2021",
month = feb,
day = "1",
doi = "10.1158/0008-5472.CAN-20-1010",
language = "English (US)",
volume = "81",
pages = "713--723",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "3",
}