DNA-PK drives CKD progression by activating TAF7/RAPTOR/mTORC1 signaling-mediated metabolic reprogramming
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Zhanjun Jia
PROVIDER: PXD030789 | iProX | Thu Jan 06 00:00:00 GMT 2022
REPOSITORIES: iProX
Publications
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives chronic kidney disease progression in male mice.
Yang Yunwen Y Liu Suwen S Wang Peipei P Ouyang Jing J Zhou Ning N Zhang Yue Y Huang Songming S Jia Zhanjun Z Zhang Aihua A
Nature communications 20230311 1
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 ...[more]
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Project description:<p>Kidney injury initiates epithelial dedifferentiation and myofibroblast activation during the progression of chronic kidney disease (CKD). Herein, we found that the expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) was significantly increased in the kidney tissues of both CKD patients and CKD mice induced by unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion (UIR) injury. In vivo, knockout of DNA-PKcs or treatment with its specific inhibitor NU7441 hampered the development of CKD in mice. In vitro, DNA-PKcs deficiency preserved epithelial cell phenotype and inhibited fibroblast activation induced by transforming growth factor-beta 1 (TGF-beta-1). Additionally, our results showed that TBP-associated factor 7 (TAF7), as a possible substrate of DNA-PKcs, enhanced mTORC1 activation by upregulating RAPTOR expression, which subsequently promoted 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 CKD, and serve as a new target for treating CKD.</p>
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