325-OR: Glucagon-Like Peptide 1 Receptor Agonists Preserved Vascular Endothelial Junction through Inhibition of STING Signaling–Elicited Inflammation in Diabetic Retinopathy

Abstract

Background: Glucagon like-peptide 1 receptor agonists (GLP-1 RAs) are protective to macrovascular diseases and nephropathy in diabetic patients; however, their role in diabetic retinopathy (DR) are still debatable. This study aimed to address the effect of GLP-1 RAs on endothelial junction and inflammation in DR. Methods: GLP-1 RAs were injected to db/db mice, then retinal inflammation and vascular changes were determined by RNA-sequencing analysis, immunostaining, fluorescein fundus imaging and Optical coherence tomography. Cross-sectional study of 1626 type 2 diabetic patients was performed. Findings: GLP-1R was majorly detected in retinal vessels, which was down-regulated by diabetes. GLP-1 RAs significantly rescued diabetes-induced retinal thinning and vascular tortuosity, likely through altered the expression profiles of junction- and mitochondria-related genes, which was confirmed by exedin-4 treatment in vitro. Stimulator of interferon genes (STING) was most abundant in the endothelial cells from fibrovascular membranes, which was positively correlated with the levels of angiogenic factors and inflammatory factors in endothelial cells from retinas with retinopathy and fibrovascular membranes. Further analysis showed prominent inhibition by GLP-1 RAs on STING activation in db/db retinas. Cross-sectional study further showed decreased DR incidence by GLP-1 RAs. Conclusions: Activation of the STING pathway induced inflammatory factors while suppressed junctional proteins in endothelial cells of DR. GLP-1 RAs ameliorated diabetes-elicited vascular damages through inhibition of the STING pathway. Disclosure X.He: None. G.Shi: None. Y.Chen: None. S.Wen: None. X.Tang: None. Z.Wen: None. R.Zhang: None. S.Li: None. R.Gao: None. Y.Zhu: None. Y.Lu: None. Funding National Natural Science Foundation of China (82000782, 82270886, 82070811); Third Affiliated Hospital of Sun Yat-sen University (2020G2RPYQN11); China International Medical Foundation (2018-N-01); Science and Technology Plan Project of Guangzhou City (202007040003)