Fig. 4 | Signal Transduction and Targeted Therapy

Fig. 4

From: Endoplasmic reticulum stress: molecular mechanism and therapeutic targets

Fig. 4

Involvement of ER stress in DR. Many factors can activate ER stress in a DR model, including hyperglycemia, hypoxia, ROS accumulation, products like LDL, AGE and MGO, and glycemia fluctuation. In pericytes, activated ER stress can induce the ATF4/CHOP pathway and then activate mitochondrial dysfunction, VEGF, and MCP-1, which facilitates leukocyte adhesion and vascular leakage. In DR, macrophages accumulate and facilitate RNV through ER stress or the IL-17A/TXNIP/NLRP3 pathway. Following ER stress, XBP1 facilitates protective anti-inflammatory and anti-neovascularization cytokines. In addition, the ATF4/ CHOP pathway to contributes inflammation, RNV production, and apoptosis of BAX, caspase 3, and PARP. The RPE cells are the most important component of the outer epithelial barrier. ER stress injures the barrier by destroying VE-cadherin and Claudin 5 through O-GlcNAcylation of VE-cadherin/Grp78, MAPK pathway, NF-κB activation and inflammation. ER stress affects the barrier directly through ROS production, mitochondrial membrane potential loss, and PEDF decrease. ATF4/SDF1α leads to RNV in RPE. Impaired autophagy and lncRNA are involved in the development of DR as well. The key enzyme of producing light-sensitive 11-cis-retinol is suppressed, which influences vision. a. retinal ganglion cell; b. amacrine cell; c. bipolar cell; d. horizontal cell; e. Müller cell; f. cone cell; g. rod cell; h. retinal pigment epithelium (RPE). The figure was created with BioRender.com (https://www.biorender.com/). DR diabetic retinopathy, LDL low density lipoprotein, AGE advanced glycation end product, MGO methylglyoxal, VEGF vascular endothelial growth factor, RNV retinal neovascularization, NLRP3 NOD-like receptor protein 3, PEDF pigment epithelium-derived factor, RPE retinal pigment epithelium

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