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

Author

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  • Yunwen Yang

    (Children’s Hospital of Nanjing Medical University
    Children’s Hospital of Nanjing Medical University
    Nanjing Medical University)

  • Suwen Liu

    (Shandong Provincial Hospital Affiliated to Shandong First Medical University)

  • Peipei Wang

    (Children’s Hospital of Nanjing Medical University
    Children’s Hospital of Nanjing Medical University
    Nanjing Medical University)

  • Jing Ouyang

    (Children’s Hospital of Nanjing Medical University
    Children’s Hospital of Nanjing Medical University
    Nanjing Medical University)

  • Ning Zhou

    (Children’s Hospital of Nanjing Medical University
    Children’s Hospital of Nanjing Medical University
    Nanjing Medical University)

  • Yue Zhang

    (Children’s Hospital of Nanjing Medical University
    Children’s Hospital of Nanjing Medical University
    Nanjing Medical University)

  • Songming Huang

    (Children’s Hospital of Nanjing Medical University
    Children’s Hospital of Nanjing Medical University
    Nanjing Medical University)

  • Zhanjun Jia

    (Children’s Hospital of Nanjing Medical University
    Children’s Hospital of Nanjing Medical University
    Nanjing Medical University)

  • Aihua Zhang

    (Children’s Hospital of Nanjing Medical University
    Children’s Hospital of Nanjing Medical University
    Nanjing Medical University)

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.

Suggested Citation

  • Yunwen Yang & Suwen Liu & Peipei Wang & Jing Ouyang & Ning Zhou & Yue Zhang & Songming Huang & Zhanjun Jia & Aihua Zhang, 2023. "DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives chronic kidney disease progression in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37043-5
    DOI: 10.1038/s41467-023-37043-5
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    References listed on IDEAS

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    1. Hui Peng & Qianqian Wang & Tanqi Lou & Jun Qin & Sungyun Jung & Vivekananda Shetty & Feng Li & Yanlin Wang & Xin-hua Feng & William E. Mitch & Brett H. Graham & Zhaoyong Hu, 2017. "Myokine mediated muscle-kidney crosstalk suppresses metabolic reprogramming and fibrosis in damaged kidneys," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    2. Mei T. Tran & Zsuzsanna K. Zsengeller & Anders H. Berg & Eliyahu V. Khankin & Manoj K. Bhasin & Wondong Kim & Clary B. Clish & Isaac E. Stillman & S. Ananth Karumanchi & Eugene P. Rhee & Samir M. Pari, 2016. "PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection," Nature, Nature, vol. 531(7595), pages 528-532, March.
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