Fyn deficiency inhibits oxidative stress by decreasing c-Cbl-mediated ubiquitination of Sirt1 to attenuate diabetic renal fibrosis.
Fyn deficiency inhibits oxidative stress by decreasing c-Cbl-mediated ubiquitination of Sirt1 to attenuate diabetic renal fibrosis.
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DOI：
10.1016/j.metabol.2022.155378
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发表时间：
2022-12
期刊：
影响因子：
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通讯作者：
Shanshan Li;Ze-yuan Lin;Hai-ming Xiao;Zhanchi Xu;Chuting Li;Jing Zeng;Xi Xie;Li Deng;Heqing Huang
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文献类型：
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作者：
Shanshan Li;Ze-yuan Lin;Hai-ming Xiao;Zhanchi Xu;Chuting Li;Jing Zeng;Xi Xie;Li Deng;Heqing Huang
目的氧化应激(OS)是导致糖尿病肾纤维化的主要原因。近年来，Fyn在OS研究中受到广泛关注，并在急性肾损伤中发挥重要作用，但Fyn在慢性糖尿病肾病(DN)中是否参与氧化应激调节尚不清楚。方法通过尾静脉注射Fyn干扰腺病毒和Fyn高表达的腺病毒，观察Fyn在糖尿病肾病中的作用。结果Fyn在高糖诱导的糖尿病小鼠肾小球系膜细胞和肾脏中表达上调。此外，Fyn基因敲除降低了HG诱导的GMCs和糖尿病小鼠肾脏中OS的水平，从而改善了糖尿病肾脏纤维化。而Fyn的过表达显著增加肾小球系膜细胞和肾组织中OS的水平，从而导致肾脏损伤。此外，Fyn缺乏通过激活Sirt1/Foxo3a途径发挥抗氧化作用。机制上，Fyn通过磷酸化c-Cbl促进c-Cb1与Sirt1的结合，从而触发c-Cbl对Lys377和Lys513的K48连锁多泛素化，并促进Sirt1的降解，从而削弱Foxo3a的抗氧化作用。结论Fyn缺乏促进Foxo3a核转录，导致c-Cbl泛素化Sirt1，从而减轻糖尿病小鼠肾脏的氧化损伤。这些结果确定Fyn是治疗糖尿病肾病的潜在靶点。
ObjectiveOxidative stress (OS) is the main cause leading to diabetic renal fibrosis. Recently, Fyn was paid much attention on OS and emerged as a pivotal player in acute kidney injury, while whether Fyn regulates oxidative stress in chronic diabetes nephropathy (DN) has not been clarified yet. The purpose of this study was to identify the role of Fyn in DN and elucidated its regulatory mechanism.MethodsThedb/dbmice and littermate control C57BKS/J mice were injected by tail vein with Fyn interfering adenovirus or Fyn overexpressing adenovirus to investigate the role of Fynin vivo. Primary glomerular mesangial cells (GMCs) were used forin vitrostudies.ResultsFyn was up-regulated in high glucose (HG)-induced GMCs and kidneys of diabetic mice. Additionally, Fyn knockdown reduced the level of OS in HG-induced GMCs and kidneys of diabetic mice, thereby ameliorating diabetic renal fibrosis. While overexpression of Fyn significantly increased the level of OS in GMCs and kidney tissues, resulting in renal damage. Moreover, Fyn deficiency exerted antioxidant effects by activating the Sirt1/Foxo3a pathway. Mechanistically, Fyn facilitated the combination of c-Cbl and Sirt1 by phosphorylating c-Cbl at Tyr731, which triggered K48-linked polyubiquitination of Sirt1 at Lys377and Lys513by c-Cbl and promoted Sirt1 degradation, impairing the antioxidant effects of Foxo3a.ConclusionsFyn deficiency promoted Foxo3a nuclear transcriptionviareducing the ubiquitination of Sirt1 by c-Cbl, thereby alleviating renal oxidative damage in diabetic mice. These results identified Fyn as a potential therapeutic target against DN.