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Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice
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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064514/ https://www.ncbi.nlm.nih.gov/pubmed/32157166 http://dx.doi.org/10.1038/s41598-020-61456-7 |
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author | 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 |
author_facet | 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 |
author_sort | Uehara, Masahiro |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7064514 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70645142020-03-18 Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice 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 Sci Rep Article 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. Nature Publishing Group UK 2020-03-10 /pmc/articles/PMC7064514/ /pubmed/32157166 http://dx.doi.org/10.1038/s41598-020-61456-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article 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 Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice |
title | Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice |
title_full | Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice |
title_fullStr | Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice |
title_full_unstemmed | Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice |
title_short | Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice |
title_sort | pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064514/ https://www.ncbi.nlm.nih.gov/pubmed/32157166 http://dx.doi.org/10.1038/s41598-020-61456-7 |
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