Department of Endocrinology, The First Affiliated Hospital for Harbin Medical University, Harbin, 150001, People's Republic of China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China.
Department of Endocrinology, The First Affiliated Hospital for Harbin Medical University, Harbin, 150001, People's Republic of China.
Mol Cell Endocrinol. 2023 Oct 1;576:112013. doi: 10.1016/j.mce.2023.112013. Epub 2023 Jul 11.
Reactive gliosis of Müller cells plays an important role in the pathogenesis of diabetic retinopathy (DR). Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been shown to improve DR by inhibiting reactive gliosis. However, the mechanism of inhibition has yet to be elucidated. This study investigated the effects of liraglutide on Müller glia reactivity in the early stages of DR and the underlying mechanisms. Proteomics combined with bioinformatics analysis, HE staining, and immunofluorescence staining revealed ganglion cell loss, reactive gliosis of Müller cells, and extracellular matrix (ECM) imbalance in rats with early stages of DR. High glucose (HG) exposure up-regulated GFAP and TNF-α expression and down-regulated ITGB1 expression and FN1 content in extracellular fluid in rMC1 cells, thereby promoting reactive gliosis. GLP-1R knockdown and HG+DAPT inhibition experiments show that liraglutide balances ECM levels by inhibiting activation of the Notch1/Hes1 pathway and ameliorates high-glucose-induced Müller glia reactivity. Thus, the study provides new targets and ideas for improvement of DR in early stages.
Müller 细胞的反应性胶质增生在糖尿病视网膜病变（DR）的发病机制中起着重要作用。胰高血糖素样肽-1 受体（GLP-1R）激动剂利拉鲁肽已被证明通过抑制反应性胶质增生来改善 DR，但抑制机制尚不清楚。本研究探讨了利拉鲁肽在 DR 早期对 Müller 胶质细胞反应性的影响及其潜在机制。蛋白质组学结合生物信息学分析、HE 染色和免疫荧光染色显示，DR 早期大鼠的神经节细胞丢失、Müller 细胞反应性胶质增生和细胞外基质（ECM）失衡。高葡萄糖（HG）暴露上调 GFAP 和 TNF-α 的表达，下调 rMC1 细胞细胞外液中 ITGB1 的表达和 FN1 含量，从而促进反应性胶质增生。GLP-1R 敲低和 HG+DAPT 抑制实验表明，利拉鲁肽通过抑制 Notch1/Hes1 通路的激活来平衡 ECM 水平，改善高糖诱导的 Müller 胶质细胞反应性。因此，该研究为改善 DR 早期阶段提供了新的靶点和思路。
