Semaglutide ameliorates retinal vascular permeability destruction in diabetic retinopathy by AnxA2-mediated MMP-9 activation and basement membrane remodeling.

作者：Chengye Xu, Ziyu Meng, Wen-Jian Lin, Hong-Xue Li, Qian Xu, Kangqi Zhao, Yangwen Chen, Yan Wang, Wei Zou, Binglin Kuang, H. Kuang · 发表于：Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 年份：2025 · DOI：10.1016/j.biopha.2025.118409 · 被引用次数：8 · 研究领域：Medicine

BACKGROUND Diabetic retinopathy (DR), a leading cause of vision loss in diabetes, is driven by basement membrane (BM) thickening and vascular hyperpermeability. While glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide exhibit pleiotropic benefits, their retinal effects remain controversial. This study investigates the mechanistic role of semaglutide in mitigating DR pathogenesis, focusing on Annexin A2 (AnxA2) and its interplay with BM remodeling. METHODS A high-fat diet/streptozotocin-induced type 2 diabetic mouse model was established. Retinal histopathology, vascular permeability (FITC-dextran), and ultrastructure (transmission electron microscopy) were evaluated. Integrated proteomics and single-cell RNA sequencing identified AnxA2 as a key regulator. Endothelial-specific AnxA2 overexpression via adeno-associated virus (AAV) and functional assays (Western blot, immunofluorescence and immunohistochemistry) elucidated its role in MMP-9 activation and BM degradation. RESULTS Diabetic mice exhibited retinal degeneration, BM thickening (P < 0.05), and elevated vascular leakage (P < 0.001). Semaglutide, but not insulin, reversed these pathologies by restoring AnxA2 expression in retinal endothelial cells (P < 0.05), thereby enhancing MMP-9 activity (P < 0.05) and collagen-IV degradation. Single-cell transcriptomics confirmed AnxA2 downregulation in diabetic endothelial cells (P = 0.027), which was rescued by semaglutide (P = 0.012). AAV-mediated AnxA2 ove...