Inhibition of ER stress mitigates hypobaric hypoxia-induced retinal damage: a simulated high-altitude study

High Altitude Retinopathy (HAR) is a pathological disorder characterized by damage to the optic nerve and retina due to hypobaric hypoxia at high altitudes. Despite its clinical importance, the underlying etiology and effective therapeutic strategies for HAR remain poorly understood and limited. In this study, we developed a murine model of acute HAR using a standardized high-altitude simulation chamber. We conducted retinal transcriptomic sequencing and bioinformatics analysis in the simulated HAR mice, with a particular focus on the significantly enriched endoplasmic reticulum (ER) stress PERK pathway. Using Western Blotting and quantitative real-time polymerase chain reaction (qRT-PCR) experiments, we verified that significant ER stress occurred in the retinas of HAR mice. Subsequently, we employed Propidium Iodide (PI)/Hoechst Staining and Flow Cytometry Analysis to demonstrate that the ER stress inhibitor Salubrinal reduced necrosis and apoptosis in mouse retinal photoreceptor cells (661W cell line) under hypoxic conditions. Furthermore, via Transmission Electron Microscopy (TEM), Optical Coherence Tomography (OCT), Hematoxylin and Eosin (H&E) staining, and Electroretinography (ERG), we confirmed that Salubrinal could alleviate hypobaric hypoxia-induced retinal edema and enhance retinal function by inhibiting the ER stress level of the PERK/eIF2α/ATF4/CHOP pathway in HAR mice. Our findings indicate that targeting the ER stress PERK pathway may be a promising therapeutic approach for managing HAR, offering potential clinical implications for treating this altitude-related ocular disorder.