Tet1 deficiency exacerbates oxidative stress in acute kidney injury by regulating superoxide dismutase

Fan, Yu; Yuan, Yangmian; Xiong, Mingrui; Jin, Muchuan; Zhang, Donge; Yang, Dong; Liu, Chengyu; Petersen, Robert B.; Huang, Kun; Peng, Anlin; Zheng, Ling

doi:10.7150/thno.87416

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Theranostics 2023; 13(15):5348-5364. doi:10.7150/thno.87416 This issue Cite

Research Paper

Tet1 deficiency exacerbates oxidative stress in acute kidney injury by regulating superoxide dismutase

Yu Fan¹, Yangmian Yuan¹, Mingrui Xiong², Muchuan Jin¹, Donge Zhang³, Dong Yang², Chengyu Liu⁴, Robert B. Petersen⁵, Kun Huang², Anlin Peng^3✉, Ling Zheng^1✉

1. Hubei Key Laboratory of Cell Homeostasis, Frontier Science Center for Immunology and Metabolism, College of Life Sciences, Wuhan University, Wuhan, China, 430072.
2. School of Pharmacy, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China, 430030.
3. Department of Pharmacy, The Third Hospital of Wuhan and Tongren Hospital of Wuhan University, Wuhan, China, 430070.
4. Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, 430030.
5. Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, MI, USA, 48858.

Citation:

Fan Y, Yuan Y, Xiong M, Jin M, Zhang D, Yang D, Liu C, Petersen RB, Huang K, Peng A, Zheng L. Tet1 deficiency exacerbates oxidative stress in acute kidney injury by regulating superoxide dismutase. Theranostics 2023; 13(15):5348-5364. doi:10.7150/thno.87416. https://www.thno.org/v13p5348.htm

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Abstract

Rationale: Increased methylation of key genes has been observed in kidney diseases, suggesting that the ten-eleven translocation (Tet) methyl-cytosine dioxygenase family as well as 5mC oxidation may play important roles. As a member of the Tet family, the role of Tet1 in acute kidney injury (AKI) remains unclear.

Methods: Tet1 knockout mice, with or without tempol treatment, a scavenger of reactive oxygen species (ROS), were challenged with ischemia and reperfusion (I/R) injury or unilateral ureteral obstruction (UUO) injury. RNA-sequencing, Western blotting, qRT-PCR, bisulfite sequencing, chromatin immunoprecipitation, immunohistochemical staining, and dot blot assays were performed.

Results: Tet1 expression was rapidly upregulated following I/R or UUO injury. Moreover, Tet1 knockout mice showed increased renal injury and renal cell death, increased ROS accumulation, G2/M cell cycle arrest, inflammation, and fibrosis. Severe renal damage in injured Tet1 knockout mice was alleviated by tempol treatment. Mechanistically, Tet1 reduced the 5mC levels in an enzymatic activity-dependent manner on the promoters of Sod1 and Sod2 to promote their expression, thus lowering injury-induced excessive ROS and reducing I/R or UUO injury.

Conclusions: Tet1 plays an important role in the development of AKI by promoting SOD expression through a DNA demethylase-dependent mechanism.

Keywords: acute kidney injury, Tet1, DNA methylation, oxidative stress, superoxide dismutase

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APA

Fan, Y., Yuan, Y., Xiong, M., Jin, M., Zhang, D., Yang, D., Liu, C., Petersen, R.B., Huang, K., Peng, A., Zheng, L. (2023). Tet1 deficiency exacerbates oxidative stress in acute kidney injury by regulating superoxide dismutase. Theranostics, 13(15), 5348-5364. https://doi.org/10.7150/thno.87416.

ACS

Fan, Y.; Yuan, Y.; Xiong, M.; Jin, M.; Zhang, D.; Yang, D.; Liu, C.; Petersen, R.B.; Huang, K.; Peng, A.; Zheng, L. Tet1 deficiency exacerbates oxidative stress in acute kidney injury by regulating superoxide dismutase. Theranostics 2023, 13 (15), 5348-5364. DOI: 10.7150/thno.87416.

NLM

CSE

Fan Y, Yuan Y, Xiong M, Jin M, Zhang D, Yang D, Liu C, Petersen RB, Huang K, Peng A, Zheng L. 2023. Tet1 deficiency exacerbates oxidative stress in acute kidney injury by regulating superoxide dismutase. Theranostics. 13(15):5348-5364.

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