Fig. 5
From: Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

Involvement of ER stress in AMD. Many risk factors contribute to AMD development, including smoke and light. The pathogenesis of AMD is closely associated with RPE death. Complement C3 can be activated and transformed into C3b to induce ER stress. The latter activated ER stress provokes the binding of C3a to C3a receptors, which amplifies the ER stress. ER stress promotes the inflammation in AMD to directly induce inflammatory factors like IL-6 and IL-8. In addition, XBP1 can provoke the protective nrf2 pathway to activate inflammation. Under ER stress, it activates caspase-4, generates ROS, elevates intracellular calcium, and reduces the mitochondrial membrane potential to promote the downstream activation of caspase-3, inducing apoptosis. Mitochondrial damage releases cytochrome c leading to RPE death. Neovascularization and ER stress influence each other through endocrine of VEGF. What’s more, decreased blood in choroid can induce hypoxia and ER stress in RPE cell and macrophages in retina. The polarization of macrophage depends on epigenic modifications of XBP1 gene which facilitates VEGF release and causes neovascularization. The figure was created with BioRender.com (https://www.biorender.com/). VEGF, vascular endothelial growth factor. AMD age-related macular degeneration, nrf2 nuclear factor erythroid2-related factor 2, RPE retinal pigment epithelium, VEGF vascular endothelial growth factor