Abstract
Purpose :
Retinal ischemia is one of the most significant pathologies in various ocular diseases, including glaucoma, diabetic retinopathy and retinal vascular occlusion, and results in the death of retinal neurons. Exchange protein activated by cAMP (Epac) is a newly identified mediator of second messenger cAMP. We previously found Epac1 plays a critical role in retinal neurodegeneration. This study aims to investigate whether Epac2, the other isoform of Epac, has a role in retinal neuronal injury in a mouse model of retinal ischemia-reperfusion (IR).
Methods :
IR was induced by elevating intraocular pressure to 110 mm Hg for 50 minutes via raising the saline reservoir, to which an infusion needle was connected and inserted into the anterior chamber of the right eyes. Retinal ganglion cells (RGCs) number, apoptosis/necroptosis, and molecules in the endoplasmic reticulum (ER) stress branches were determined by immunohistochemistry and TUNEL assay.
Results :
We found that at 12 hours after IR, retinal neuronal apoptosis (TUNEL-positive cells) and necroptosis (p-RIP3-positve cells) were dramatically increased in wild type (WT) IR retinas, which were significantly mitigated by Epac2 genetic deletion. At 7 days after IR, RGCs were significantly preserved in Epac2-/- mice compared with age-matched WT mice. Mechanistically, the expressions of ER stress-related molecules including GRP78, p-PERK and CHOP, and ER stress response mediator ER oxidoreductin 1 (ERO1α) were significantly increased after ischemic injury and Epac2 deletion lowered levels of p-PERK, CHOP and ERO1 whose activation can lead to cell death.
Conclusions :
These data indicate that Epac2 deletion is neuroprotective against retinal IR injury through attenuation of ER stress, and Epac2 blockade may be a favorable strategy in the treatment of retinal neurodegenerative diseases.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.