视网膜变性以米勒细胞神经胶质增生和光感受器凋亡为特征，被认为是糖尿病视网膜病变 (DR) 的早期事件。我们之前的研究提出GMFB可能介导糖尿病性视网膜变性。本研究确定 GMFB 是 DR 的敏感且功能性神经胶质增生标记物。与野生型（WT）组相比，Gmfb敲除（KO）显着改善视功能，减弱神经胶质增生，减少神经元凋亡，并降低肿瘤坏死因子α（Tnf-α）和白介素-1β（II）的mRNA水平-1β）在糖尿病视网膜中。使用原代 WT 和 KO Müller 细胞中的 RNA 测序，通过 hub 基因富集 Tgf-β3。 Gmfb KO 通过 AKT 途径显着上调转化生长因子 (TGF)-β3 蛋白水平。玻璃体中TGF-β3的保护作用可显着改善糖尿病视网膜中的视觉功能并减少凋亡细胞的数量。原代 Müller 细胞中 Gmfb KO 对高葡萄糖 (HG) 诱导的光感受器细胞凋亡的保护作用被 TGF-β3 抗体和 TGFBR1/2 抑制剂的施用部分抵消。核受体亚家族 3 C 组成员 1 (NR3C1) 与 Gmfb 的启动子区域结合并在转录水平调节 Gmfb mRNA。 NR3C1在早期糖尿病大鼠的视网膜中增加，但在晚期糖尿病大鼠的视网膜中减少。 N'-[(1E)-(3-甲氧基苯基)亚甲基]-3-甲基-1H-吡唑-5-碳酰肼 (DS-5) 被确定为 GMFB 抑制剂，对 DR 具有保护作用。我们证明 GMFB/AKT/TGF-β3 介导糖尿病大鼠的早期糖尿病视网膜变性。这项研究为治疗 DR 患者的视网膜变性提供了一种新的治疗策略。© 2023 Wiley periodicals LLC。

Retinal degeneration, characterized by Müller cell gliosis and photoreceptor apoptosis, is considered an early event in diabetic retinopathy (DR). Our previous study proposed that GMFB may mediate diabetic retinal degeneration. This study identified GMFB as a sensitive and functional gliosis marker for DR. Compared to the wild type (WT) group, Gmfb knockout (KO) significantly improved visual function, attenuated gliosis, reduced the apoptosis of neurons, and decreased the mRNA levels of tumor necrosis factor α (Tnf-α) and interleukin-1β (Il-1β) in diabetic retinas. Tgf-β3 was enriched by hub genes using RNA sequencing in primary WT and KO Müller cells. Gmfb KO significantly upregulated the transforming growth factor (TGF)-β3 protein level via the AKT pathway. The protective effect of TGF-β3 in the vitreous resulted in significantly improved visual function and decreased the number of apoptotic cells in the diabetic retina. The protection of Gmfb KO in primary Müller cells against high glucose (HG)-induced photoreceptor apoptosis was partially counteracted by TGF-β3 antibody and administration of TGFBR1/2 inhibitors. Nuclear receptor subfamily 3 group C member 1 (NR3C1) binds to the promoter region of Gmfb and regulates Gmfb mRNA at the transcriptional level. NR3C1 was increased in the retinas of early diabetic rats but decreased in the retinas of late diabetic rats. N'-[(1E)-(3-Methoxyphenyl)Methylene]-3-Methyl-1H-Pyrazole-5-Carbohydrazide (DS-5) was identified as an inhibitor of GMFB, having a protective role in DR. We demonstrated that GMFB/AKT/TGF-β3 mediated early diabetic retinal degeneration in diabetic rats. This study provides a novel therapeutic strategy for treating retinal degeneration in patients with DR.© 2023 Wiley Periodicals LLC.