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; Aihua Zhang

doi:10.1038/s41467-023-37043-5

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

Nat Commun. 2023 Mar 11;14(1):1334. doi: 10.1038/s41467-023-37043-5.

Authors

Yunwen Yang^{1

2

3}, Suwen Liu⁴, Peipei Wang^{1

2

3}, Jing Ouyang^{1

2

3}, Ning Zhou^{1

2

3}, Yue Zhang^{5

6

7}, Songming Huang^{8

9

10}, Zhanjun Jia^{11

12

13}, Aihua Zhang^{14

15

16}

Affiliations

¹ Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, 210008, China.
² Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
³ Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China.
⁴ Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
⁵ Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, 210008, China. zyflora2006@hotmail.com.
⁶ Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. zyflora2006@hotmail.com.
⁷ Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. zyflora2006@hotmail.com.
⁸ Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, 210008, China. smhuang@njmu.edu.cn.
⁹ Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. smhuang@njmu.edu.cn.
¹⁰ Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. smhuang@njmu.edu.cn.
¹¹ Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, 210008, China. jiazj72@hotmail.com.
¹² Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. jiazj72@hotmail.com.
¹³ Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. jiazj72@hotmail.com.
¹⁴ Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing, 210008, China. zhaihua@njmu.edu.cn.
¹⁵ Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China. zhaihua@njmu.edu.cn.
¹⁶ Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. zhaihua@njmu.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Catalytic Domain
DNA
DNA-Activated Protein Kinase* / metabolism
Kidney / metabolism
Male
Mechanistic Target of Rapamycin Complex 1 / metabolism
Mice
Renal Insufficiency, Chronic*

Substances

DNA-Activated Protein Kinase
Mechanistic Target of Rapamycin Complex 1
DNA