FIG. 8.

Schematic diagram showing the mechanisms of ER stress regulating inflammatory gene expression in retinal Müller cells. Diabetic insults such as hyperglycemia and hypoxia induce ER stress in retinal cells, including Müller cells. Unrelieved ER stress upregulates ATF4, which directly binds to promoters of inflammatory genes (e.g., VEGF), interacts and stabilizes HIF-1α, and activates JNK, resulting in exaggerated and sustained expression of inflammatory genes. Increased inflammatory cytokines promote leukostasis and endothelial activation, leading to breakdown of the blood-retinal barrier, vascular leakage, and diabetic macular edema.