Hou Zixin, Chen Ji, Yang Huan, Hu Xiaoling, Yang Fengrui
Department of Anesthesiology, The First Affiliated Hospital of University of South China, Hengyang, 421001, P.R. China.
Department of Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, P.R. China.
Cell Death Discov. 2021 Dec 2;7(1):372. doi: 10.1038/s41420-021-00765-w.
Diabetic peripheral neuropathy (DPN) is a frequently occurring chronic complication of diabetes. In this study, we aim to explore the regulatory mechanism of protein inhibitor of activated STAT1 (PIAS1) in DPN in terms of autophagy and apoptosis of Schwann cells. The SUMOlation of PPAR-γ by PIAS1 was examined, and ChIP was performed to verify the binding of PPAR-γ to miR-124 promoter region. Dual-luciferase gene reporter assay was used to validate the binding affinity between miR-124 and EZH2/STAT3. Following loss- and gain-of-function experiments, in vitro assays in high glucose-treated Schwann cells (SC4) and in vivo assays in db/db and ob/ob mice were performed to detect the effects of PIAS1 on autophagy and apoptosis of Schwann cells as well as symptoms of DPN by regulating the PPAR-γ-miR-124-EZH2/STAT3. The expression of PIAS1, PPAR-γ, and miR-124 was downregulated in the sciatic nerve tissue of diabetic mice. PIAS1 enhanced the expression of PPAR-γ through direct binding and SUMOlation of PPAR-γ. PPAR-γ enhanced the expression of miR-124 by enhancing the promoter activity of miR-124. Furthermore, miR-124 targeted and inversely modulated EZH2 and STAT3, promoting the autophagy of Schwann cells and inhibiting their apoptosis. In vivo experiments further substantiated that PIAS1 could promote the autophagy and inhibit the apoptosis of Schwann cells through the PPAR-γ-miR-124-EZH2/STAT3 axis. In conclusion, PIAS1 promoted SUMOlation of PPAR-γ to stabilize PPAR-γ expression, which upregulated miR-124 to inactivate EZH2/STAT3, thereby inhibiting apoptosis and promoting autophagy of Schwann cells to suppress the development of DPN.
糖尿病周围神经病变（DPN）是糖尿病常见的慢性并发症。在本研究中，我们旨在从雪旺细胞自噬和凋亡方面探讨信号转导和转录激活因子1（STAT1）蛋白抑制剂（PIAS1）在DPN中的调控机制。检测了PIAS1对过氧化物酶体增殖物激活受体γ（PPAR-γ）的小泛素样修饰（SUMO化），并进行染色质免疫沉淀（ChIP）以验证PPAR-γ与miR-124启动子区域的结合。采用双荧光素酶基因报告基因检测法验证miR-124与EZH2/STAT3之间的结合亲和力。在功能缺失和功能获得实验之后，对高糖处理的雪旺细胞（SC4）进行体外实验，并对db/db和ob/ob小鼠进行体内实验，以检测PIAS1通过调节PPAR-γ-miR-124-EZH2/STAT3对雪旺细胞自噬和凋亡以及DPN症状的影响。糖尿病小鼠坐骨神经组织中PIAS1、PPAR-γ和miR-124的表达下调。PIAS1通过直接结合和对PPAR-γ进行SUMO化增强PPAR-γ的表达。PPAR-γ通过增强miR-124的启动子活性来增强miR-124的表达。此外，miR-124靶向并反向调节EZH2和STAT3，促进雪旺细胞自噬并抑制其凋亡。体内实验进一步证实，PIAS1可通过PPAR-γ-miR-124-EZH2/STAT3轴促进雪旺细胞自噬并抑制其凋亡。总之，PIAS1促进PPAR-γ的SUMO化以稳定PPAR-γ表达，上调miR-124使EZH2/STAT3失活，从而抑制雪旺细胞凋亡并促进其自噬，以抑制DPN的发展。
