胶质增生
视网膜变性
生物
转化生长因子
内分泌学
内科学
蛋白激酶B
视网膜
细胞凋亡
视网膜
细胞生物学
信号转导
医学
生物化学
神经科学
作者
Tong Zhu,Yingao Li,Lilin Zhu,Jinyuan Xu,Zijun Feng,Hao Chen,Si Shi,Caiying Liu,Qingjian Ou,Furong Gao,Jieping Zhang,Caixia Jin,Jingying Xu,Jiao Li,Jingfa Zhang,Yanlong Bi,Guo‐Tong Xu,Juan Wang,Haibin Tian,Lixia Lü
出处
期刊:Glia
[Wiley]
日期:2023-10-31
卷期号:72 (3): 504-528
摘要
Abstract 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.
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