Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice

• Published in: Scientific reports 2020-03, Vol.10 (1), p.4441-4441, Article 4441
• Main Authors: Uehara, Masahiro, Kusaba, Tetsuro, Ida, Tomoharu, Nakai, Kunihiro, Nakata, Tomohiro, Tomita, Aya, Watanabe-Uehara, Noriko, Ikeda, Kisho, Kitani, Takashi, Yamashita, Noriyuki, Kirita, Yuhei, Matoba, Satoaki, Humphreys, Benjamin D., Tamagaki, Keiichi
• Format: Article
• Language: English
• Subjects: 64/60; 692/4022/1585/3182; 692/4022/1585/4; 82/1; 82/80; 96/2; 96/21; 96/95; Apoptosis; Ataxia; Cell cycle; Cisplatin; Cytokines; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Epithelial cells; Fanconi syndrome; Fibrosis; Flow cytometry; Humanities and Social Sciences; Kidneys; Mitochondria; multidisciplinary; p53 Protein; Paracrine signalling; Phosphorylation; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-61456-7

The DNA damage response after kidney injury induces cell cycle arrest in renal tubular epithelial cells, resulting in the secretion of pro-fibrotic cytokines, thereby promoting interstitial fibrosis in a paracrine manner. Phosphorylation of ataxia-telangiectasia mutated (ATM) is the initial step in the DNA damage response and subsequent cell cycle arrest; however, the effects of ATM inhibition on the injured kidney have not been explored. Pharmacological ATM inhibition by KU55933 in cisplatin-treated mice did not ameliorate, but instead exacerbated cisplatin-induced DNA damage and tubular injury, thereby increasing mortality. Analysis of isolated tubular epithelia by FACS from bigenic SLC34a1-CreERt2; R26tdTomato proximal tubular-specific reporter mice revealed that KU55933 upregulated p53 and subsequent pro-apoptotic signaling in tubular epithelia of cisplatin-treated mice, leading to marked mitochondrial injury and apoptosis. In addition, KU55933 attenuated several DNA repair processes after cisplatin treatment, including single-strand DNA repair and Fanconi anemia pathways, suggesting that DNA repair after dual treatment of cisplatin and KU55933 was not sufficient to prevent the cisplatin-induced tubular injury. Our study suggested that ATM inhibition does not increase DNA repair after cisplatin-induced DNA damage and exacerbates tubular injury through the upregulation of p53-dependent pro-apoptotic signaling. Acute kidney injury must be carefully monitored when ATM inhibitors become available in clinical practice in the future.