Down-regulation of GRP78 enhances apoptosis via CHOP pathway in retinal ischemia-reperfusion injury

Ischemia/reperfusion (I/R) injury is the main cause of retinal apoptosis. But the mechanism remains elusive. During I/R injury, the intracellular calcium levels increase, resulting in the generation of reactive oxygen species, which have been shown to cause endoplasmic reticulum (ER) stress. However, little is known about the correlation between apoptosis and ER stress in retinal I/R injury. In the present study, we demonstrated that ER stress was activated in the retina of rat I/R models. The transcriptional expression of ER stress-associated molecules, glucose-regulated protein-78 (GRP78) and C/EBP-homologous protein (CHOP) were significantly increased in I/R retinas in a time-dependent manner. Partial inhibition of the endogenous expression of GRP78 with antisense oligonucleotide resulted in significant retinal damage and apoptosis in I/R injury rats. Also, the transcriptional expression of CHOP was persistently increased. Our findings indicate that ER stress may play a critical role in I/R injury induced retinal damage, and GRP78 may exert anti-apoptotic actions in I/R retina. Importantly, the persistent high expression of CHOP might serve as a possible mechanism that contributes to the enhanced the I/R-induced apoptosis after GRP78 down-regulation. These results may provide insight into the pathology of retinal I/R injury.