2. Academic Validation
  3. Connexin32 promotes the activation of Foxo3a to ameliorate diabetic nephropathy via inhibiting the polyubiquitination and degradation of Sirt1

Connexin32 promotes the activation of Foxo3a to ameliorate diabetic nephropathy via inhibiting the polyubiquitination and degradation of Sirt1

  • Antioxid Redox Signal. 2023 Jan 5. doi: 10.1089/ars.2022.0108.
Shanshan Li 1,  Haiming Xiao 2,  Xiaohong Sun 3,  Zhiquan Chen 4,  Zeyuan Lin 5,  Chuting Li 6,  Jingran Zeng 7,  Zhanchi Xu 8,  Yuanyuan Cheng 9,  Heqing Huang 10
Affiliations

Affiliations

  • 1 Sun Yat-Sen University, 26469, GuangZhou, GuangZhou, GuangDong, China, 510275; 2532315143@qq.com.
  • 2 Sun Yat-Sen University, 26469, Guangzhou, China, Guangzhou, China, 510275; 1252881814@qq.com.
  • 3 Shenzhen Children's Hospital, 85113, Shenzhen, Guangdong, China; 120919500@qq.com.
  • 4 Guangxi Medical University, 74626, Nanning, Guangxi, China; chenzhiquan@stu.gxmu.edu.cn.
  • 5 Sun Yat-Sen University, 26469, Guangzhou, Guangdong, China; linzy9@mail2.sysu.edu.cn.
  • 6 Sun Yat-Sen University, 26469, Guangzhou, Guangdong, China; licht7@mail2.sysu.edu.cn.
  • 7 Sun Yat-Sen University, 26469, Guangzhou, Guangdong, China; 416255957@qq.com.
  • 8 Sun Yat-Sen University, 26469, Guangzhou, Guangdong, China; xuzhch25@mail.sysu.edu.cn.
  • 9 Guangzhou University of Chinese Medicine, 47879, Guangzhou, Guangdong, China; chengyuanyuan@gzucm.edu.cn.
  • 10 Sun Yat-sen University, Laboratory of Pharmacology & Toxicology, guangzhou , guangdong, China; huangheq@mail.sysu.edu.cn.
PMID: 36601735 DOI: 10.1089/ars.2022.0108
Abstract

Aims: Renal oxidative stress is the leading cause of diabetic nephropathy (DN). The SIRT1/Foxo3a pathway plays an essential role in regulating the antioxidant Enzyme system. Here, we aimed to investigate the mechanism of Cx32 on antioxidant Enzyme system in DN.

Results: In this study, Cx32 overexpression significantly reduced ROS generation and effectively inhibited the excessive production of extracellular matrix such as FN and ICAM-1 in high glucose (HG)-induced GMCs. Additionally, Cx32 overexpression reversed the down-regulation of SIRT1, and promoted the nuclear transcription of Foxo3a, subsequently activating the antioxidant Enzymes including catalase and MnSOD，however, Cx32 knockdown showed the opposite effects. Further mechanism study showed that Cx32 promoted the auto-ubiquitination and degradation of Smurf1, thereby reducing the ubiquitination of SIRT1 at Lys335 and the degradation of SIRT1. Moreover, the in vivo results showed that adenovirus-mediated Cx32 overexpression activated the SIRT1/Foxo3a pathway, and inhibited oxidative stress in the kidney tissues, eventually improving the renal function and glomerulosclerosis in diabetic mice.

Innovation: This study highlighted the antioxidant role of Cx32-Sirt1-Foxo3a axis to alleviate DN, which is a new mechanism of Cx32 alleviating DN.

Conclusion: Cx32 alleviated DN via activating the SIRT1/Foxo3a antioxidant pathway. The specific mechanism was that Cx32 upregulated the SIRT1 expression through reducing the ubiquitination of Lys335 of SIRT1 by inhibiting Smurf1.

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