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Updated: Aug 12, 2026
A Mouse Model of Retinal Ischemia-Reperfusion Injury Through Elevation of Intraocular Pressure
Published on: July 14, 2016
Exosomal miR-450b-5p Secreted from Exendin-4-Stimulated Endothelial Cells Protects Retinal Ganglion Cells Against
Yanan Sun1,2, Ruyi Zhai1, Qilian Sheng1
1Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, National Health Commission Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, People's Republic of China.
Background:
Retinal ischemia-reperfusion (RIR) injury represents a critical pathophysiological mechanism underlying various ocular ischemic diseases, characterized by progressive loss of retinal ganglion cells (RGCs). Exendin-4 (Ex-4), a widely used glucagon-like peptide-1 receptor (GLP-1R) agonist drug in the treatment of type 2 diabetes mellitus, has been reported to protect against ischemia-reperfusion (IR) injury in various vital organs. However, the potential neuroprotective effect of Ex-4 under RIR injury has been poorly understood.
Methods:
Immunofluorescence staining assay, hematoxylin and eosin (HE) staining were conducted to evaluate the neuroprotective role of Ex-4. A co-culture assay of human retinal vascular endothelial cells (HRVECs) and RGCs was established. Extracellular vesicles (EVs) were isolated from the culture supernatant of HRVECs with (E-EVs) or without Ex-4 treatment (O-EVs) under oxygen-glucose deprivation/reoxygenation (OGD/R) condition. Transmission electron microscopy (TEM), Nanoparticle tracking analysis (NTA) and Nano-flow cytometry (NanoFCM) were used to detect the presence and purity of EVs. Cell activity, reactive oxygen species (ROS) level, and cell death rate of RGCs were evaluated. Further global miRNA sequencing was performed on E-EVs or O-EVs to explore potential mechanisms.
Results:
Our findings revealed that Ex-4 had a GLP-1R-dependent neuroprotective effect on RGCs. Vascular endothelial cells (VECs) -derived EVs mediate the protective effect of Ex-4 on RGCs under acute RIR injury. We identified miR-450b-5p as a highly enriched miRNA in E-EVs. Treatment with either E-EVs or miR-450b-5p mimics significantly protected RGCs against RIR-induced injury. Mechanistic investigations identified acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) as a direct target of miR-450b-5p.
Conclusion:
Ex-4 exerts its neuroprotective effects under RIR injury by stimulating retinal VECs to secrete miR-450b-5p-enriched EVs, thereby revealing a novel endothelial-mediated neuroprotective pathway in ischemia diseases.
