DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives chronic kidney disease progression in male mice

Kidney injury initiates epithelial dedifferentiation and myofibroblast activation during the progression of chronic kidney disease. Herein, we find that the expression of DNA-PKcs is significantly increased in the kidney tissues of both chronic kidney disease patients and male mice induced by unilateral ureteral obstruction and unilateral ischemia-reperfusion injury. In vivo, knockout of DNA-PKcs or treatment with its specific inhibitor NU7441 hampers the development of chronic kidney disease in male mice. In vitro, DNA-PKcs deficiency preserves epithelial cell phenotype and inhibits fibroblast activation induced by transforming growth factor-beta 1. Additionally, our results show that TAF7, as a possible substrate of DNA-PKcs, enhances mTORC1 activation by upregulating RAPTOR expression, which subsequently promotes metabolic reprogramming in injured epithelial cells and myofibroblasts. Taken together, DNA-PKcs can be inhibited to correct metabolic reprogramming via the TAF7/mTORC1 signaling in chronic kidney disease, and serve as a potential target for treating chronic kidney disease.


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March 2021
identifier PXD030789 (http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD030789). Mass spectrometry analysis of in vitro kinase assay has also been submitted to iProX with the identifier PXD036930 (http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD036930). Metabolomics data of kidney tissues have been submitted to metabolights (www.ebi.ac.uk/metabolights/MTBLS5971). All the data of this study are available within the article, the Supplementary Information file, the Source data file, as described in the Reporting summary of this article. Source data are provided with this study.

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In this study, total 15 injured kidney samples obtained from patients with renal fibrosis (Both male and female patients were recruited, the clinical parameters of the patients are listed in Supplementary

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In this study, the kidney samples of patients with renal fibrosis were collected between 2019 and 2020 at Children's Hospital of Nanjing Medical University. The patients who were diagnosed with renal fibrosis at Children's Hospital of Nanjing Medical University between 2019 and 2020 were all recruited, all the patients (their parents/guardians) agreed to participation for free, so self-selection bias is low.

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The protocol concerning the use of human kidney biopsy samples in this study was approved by the Committee on Research Ethics of Children's Hospital of Nanjing Medical University and informed consent was obtained from all human study participants (or their parents/guardians) Note that full information on the approval of the study protocol must also be provided in the manuscript.

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