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

Yunwen Yang, Suwen Liu, Peipei Wang, Jing Ouyang, Ning Zhou, Yue Zhang (), Songming Huang (), Zhanjun Jia () and Aihua Zhang ()
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Yunwen Yang: Children’s Hospital of Nanjing Medical University
Suwen Liu: Shandong Provincial Hospital Affiliated to Shandong First Medical University
Peipei Wang: Children’s Hospital of Nanjing Medical University
Jing Ouyang: Children’s Hospital of Nanjing Medical University
Ning Zhou: Children’s Hospital of Nanjing Medical University
Yue Zhang: Children’s Hospital of Nanjing Medical University
Songming Huang: Children’s Hospital of Nanjing Medical University
Zhanjun Jia: Children’s Hospital of Nanjing Medical University
Aihua Zhang: Children’s Hospital of Nanjing Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37043-5

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