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.
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DOI：
10.1089/ars.2022.0108
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发表时间：
2023-01
影响因子：
6.6
通讯作者：
Shanshan Li;Hai-ming Xiao;Xiao-hong Sun;Zhi-quan Chen;Ze-yuan Lin;Chuting Li;Jing Zeng;
中科院分区：
文献类型：
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作者：
Shanshan Li;Hai-ming Xiao;Xiao-hong Sun;Zhi-quan Chen;Ze-yuan Lin;Chuting Li;Jing Zeng;
目的肾脏氧化应激是糖尿病肾病(DN)的主要原因。Sirt1/Foxo3a通路在调节抗氧化酶系统中起着至关重要的作用。本研究旨在探讨Cx32对糖尿病肾病患者抗氧化酶系统的作用机制。结果在本研究中，Cx32过表达显著减少高糖诱导的GMCs产生ROS，并有效抑制细胞外基质FN和ICAM-1的过度产生。此外，Cx32的过表达逆转了Sirt1的下调，促进了Foxo3a的核转录，从而激活了包括过氧化氢酶和MnSOD在内的抗氧化酶，而Cx32的过表达则表现出相反的作用。进一步的机制研究表明，Cx32促进了SMurf1的自身泛素化和降解，从而减少了Sirt1在Lys335的泛素化和Sirt1的降解。体内实验结果表明，腺病毒介导的Cx32过表达激活了Sirt1/Foxo3a途径，抑制了肾脏组织中的氧化应激，最终改善了糖尿病小鼠的肾功能和肾小球硬化。本研究突出了Cx32-Sirt1-Foxo3a轴在减轻糖尿病肾病中的抗氧化作用，这是Cx32减轻糖尿病肾病的新机制。结论Cx32通过激活Sirt1/Foxo3a抗氧化通路减轻糖尿病肾病。其具体机制是Cx32通过抑制SMurf1而降低Sirt1的Lys335泛素化，从而上调Sirt1的表达。
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.