GMFB/AKT/TGF-β3 in Müller cells mediated early retinal degeneration in a streptozotocin-induced rat diabetes model.
Tong ZhuYingao LiLilin ZhuJinyuan XuZijun FengHao ChenSi ShiCaiying LiuQingjian OuFurong GaoJieping ZhangCaixia JinJingying XuJiao LiJingfa ZhangYanlong BiGuo-Tong XuJuan WangHaibin TianLixia LvPublished in: Glia (2023)
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.
Keyphrases
- diabetic rats
- oxidative stress
- induced apoptosis
- diabetic retinopathy
- transforming growth factor
- cell cycle arrest
- optical coherence tomography
- cell death
- epithelial mesenchymal transition
- signaling pathway
- high glucose
- endoplasmic reticulum stress
- type diabetes
- pi k akt
- cell proliferation
- optic nerve
- endothelial cells
- rheumatoid arthritis
- cardiovascular disease
- gene expression
- editorial comment
- wild type
- mesenchymal stem cells
- bone marrow
- spinal cord injury
- spinal cord
- molecular dynamics simulations
- glycemic control
- binding protein
- insulin resistance
- cell therapy