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  2. BRG1 accelerates mesothelial cell senescence and peritoneal fibrosis by inhibiting mitophagy through repression of OXR1

BRG1 accelerates mesothelial cell senescence and peritoneal fibrosis by inhibiting mitophagy through repression of OXR1

  • Free Radic Biol Med. 2024 Feb 2:214:54-68. doi: 10.1016/j.freeradbiomed.2024.01.054.
Shuting Li 1 Yiyi Zhuang 2 Yue Ji 2 Xiaowen Chen 2 Liying He 2 Sijia Chen 3 Yating Luo 2 Lingyu Shen 2 Jing Xiao 2 Huizhen Wang 2 Congwei Luo 4 Fenfen Peng 5 Haibo Long 6
Affiliations

Affiliations

  • 1 Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Department of Nephrology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China.
  • 2 Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 3 Department of Nephrology and Rheumatology, The First Hospital of Changsha, Changsha, China.
  • 4 Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, China. Electronic address: 116505078@qq.com.
  • 5 Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, China. Electronic address: doctorpff@163.com.
  • 6 Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, China. Electronic address: longhb1966@163.com.
Abstract

Peritoneal mesothelial cell senescence promotes the development of peritoneal dialysis (PD)-related peritoneal fibrosis. We previously revealed that Brahma-related gene 1 (BRG1) is increased in peritoneal fibrosis yet its role in modulating peritoneal mesothelial cell senescence is still unknown. This study evaluated the mechanism of BRG1 in peritoneal mesothelial cell senescence and peritoneal fibrosis using BRG1 knockdown mice, primary peritoneal mesothelial cells and human peritoneal samples from PD patients. The augmentation of BRG1 expression accelerated peritoneal mesothelial cell senescence, which attributed to mitochondrial dysfunction and Mitophagy inhibition. Mitophagy Activator salidroside rescued fibrotic responses and cellular senescence induced by BRG1. Mechanistically, BRG1 was recruited to oxidation resistance 1 (OXR1) promoter, where it suppressed transcription of OXR1 through interacting with forkhead box protein p2. Inhibition of OXR1 abrogated the improvement of BRG1 deficiency in Mitophagy, fibrotic responses and cellular senescence. In a mouse PD model, BRG1 knockdown restored Mitophagy, alleviated senescence and ameliorated peritoneal fibrosis. More importantly, the elevation level of BRG1 in human PD was associated with PD duration and D/P creatinine values. In conclusion, BRG1 accelerates mesothelial cell senescence and peritoneal fibrosis by inhibiting Mitophagy through repression of OXR1. This indicates that modulating BRG1-OXR1-mitophagy signaling may represent an effective treatment for PD-related peritoneal fibrosis.

Keywords

Brahma-related gene 1; Mesothelial-to-mesenchymal transition; Mitophagy; Oxidation resistance 1; Peritoneal dialysis; Peritoneal fibrosis.

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