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.

The prevalence of renal diseases including acute kidney injury (AKI) and chronic kidney disease (CKD) is increasing worldwide. However, the pathogenesis of most renal diseases is still unclear and effective treatments are still lacking. DNA damage and the related DNA damage response (DDR) have been confirmed as common pathogenesis of acute kidney injury and chronic kidney disease. Reactive oxygen species (ROS) induced DNA damage is one of the most common types of DNA damage involved in the pathogenesis of acute kidney injury and chronic kidney disease. In recent years, several developments have been made in the field of DNA damage. Herein, we review the roles and developments of DNA damage and DNA damage response in renal tubular epithelial cell injury in acute kidney injury and chronic kidney disease. In this review, we conclude that focusing on DNA damage and DNA damage response may provide valuable diagnostic biomarkers and treatment strategies for renal diseases including acute kidney injury and chronic kidney disease.