机构：[1]Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China[2]Dept of Pharmacy, Shenzhen Children’s Hospital, Shenzhen, Guangdong 518026, China[3]School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China[4]Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning 530021, China
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.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.This study highlighted the antioxidant role of Cx32-Sirt1-Foxo3a axis to alleviate DN, which is a new mechanism of Cx32 alleviating DN.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.
基金：
This work was supported by the National Natural Science Foundation of China (grant
number 81973375), Guangdong Key Areas R&D Program Projects (grant number 2020B1111100004) and the Project of Improving the Basic Scientific Research Ability of
Young and Middle-aged Teachers in Guangxi Universities (grant number 2022KY0076).
第一作者机构：[1]Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Li Shanshan,Xiao Haiming,Sun Xiaohong,et al.Connexin32 promotes the activation of Foxo3a to ameliorate diabetic nephropathy via inhibiting the polyubiquitination and degradation of Sirt1[J].ANTIOXIDANTS & REDOX SIGNALING.2023,39(4-6):241-261.doi:10.1089/ars.2022.0108.
APA：
Li Shanshan,Xiao Haiming,Sun Xiaohong,Chen Zhiquan,Lin Zeyuan...&Huang Heqing.(2023).Connexin32 promotes the activation of Foxo3a to ameliorate diabetic nephropathy via inhibiting the polyubiquitination and degradation of Sirt1.ANTIOXIDANTS & REDOX SIGNALING,39,(4-6)
MLA：
Li Shanshan,et al."Connexin32 promotes the activation of Foxo3a to ameliorate diabetic nephropathy via inhibiting the polyubiquitination and degradation of Sirt1".ANTIOXIDANTS & REDOX SIGNALING 39..4-6(2023):241-261
生物学