![]() ![]() Recently, emerging evidence has demonstrated the relationship between metabolic dysregulation and interstitial fibrosis, revealing that metabolic reprogramming occurs in kidney cells (renal tubular epithelial cells 8, 9 and myofibroblasts 10) during kidney injury and contributes to the development of CKD. ![]() As a key mediator of interstitial fibrosis, TGF-β1 not only activates the expression of fibrotic genes, including α-smooth muscle actin (α-SMA), fibronectin (FN) and collagens, but also promotes Warburg effect-like metabolic reprogramming of kidney cells 6, 7. In injured kidneys, interstitial fibrosis involves the abnormal expression of profibrotic factors, such as transforming growth factor-beta 1 (TGF-β1), epithelial dedifferentiation and myofibroblast activation 2. There are no effective treatments for CKD, highlighting an urgent need for a better understanding of the pathological mechanisms underlying CKD. Many of the pathophysiological features of kidney fibrosis are shared by other fibrotic diseases, such as liver cirrhosis and cardiomyopathies 5. Renal interstitial fibrosis is one of the major pathological characteristics of CKD 2, 3, 4. CKD poses a huge burden on global public health, as it has a high likeliness to progress into end-stage renal disease (ESRD), which requires dialysis or kidney transplantation 1, 2. Similar content being viewed by othersĬhronic kidney disease (CKD) inflicts on 10% of the adults worldwide 1. 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. 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. In vitro, DNA-PKcs deficiency preserves epithelial cell phenotype and inhibits fibroblast activation induced by transforming growth factor-beta 1. In vivo, knockout of DNA-PKcs or treatment with its specific inhibitor NU7441 hampers the development of chronic kidney disease in male mice. 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. Kidney injury initiates epithelial dedifferentiation and myofibroblast activation during the progression of chronic kidney disease. ![]()
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