Sigma-1 Receptor Activation Alleviates iBRB Dysfunction after I/R Injury by Inhibiting Endoplasmic Reticulum Stress-Dependent Autophagy.

To explore the potential protective role and underlying mechanism of the sigma-1 receptor (σ1R) on inner blood-retinal barrier (iBRB) function after retinal ischemia/reperfusion (I/R) injury. A retinal I/R injury model was established in C57BL/6 mice, and the protective effects of σ1R were evaluated using the σ1R agonist SA4503 and the antagonist BD1047. In vitro, an oxygen-glucose deprivation/reperfusion (OGD/R) cell model was used to investigate the regulatory role of σ1R on ER stress, autophagy, and tight junction (TJ) proteins via Western blotting, immunofluorescence, and fluorescently labeled autophagic flux assays. Specific activators and inhibitors of ER stress and autophagy were also employed to elucidate the mechanism of σ1R regulation. Activating σ1R with the agonist SA4503 notably decreased Evans blue leakage in vivo and prevented the disassembly of tight junction proteins both in vivo and in vitro. These advantageous effects disappeared when pretreated with the σ1R antagonist BD1047. σ1R activation mitigated I/R-induced endoplasmic reticulum (ER) stress and autophagy, but these protective benefits were nullified by the administration of tunicamycin (an ER stress activator) or rapamycin (an autophagy activator). Tunicamycin inhibited SA4503's effects on ER stress and autophagy, while rapamycin specifically blocked SA4503's impact on autophagy. Furthermore, an ER stress inhibitor (4-phenylbutyrate) and inhibitors of ER-related signaling pathways (ATF6 inhibitor, IRE1 inhibitor, and PERK inhibitor) effectively blocked I/R-induced autophagy. Activating σ1R had protective effects on iBRB and capillary endothelial function after retinal I/R injury. These effects might involve inhibition of ER stress-dependent autophagy and the degradation of tight junction proteins.