PERK inhibition suppresses neovascularization and protects neurons during ischemia-induced retinopathy

Abstract

Purpose : Retinal ischemia is a common cause of a variety of eye diseases, including diabetic retinopathy, thrombotic vein occlusion, and retinopathy of prematurity. Protein kinase RNA-activated like endoplasmic reticulum (ER) kinase (PERK), one of the major ER stress sensor proteins, has been implicated in various diseases. The goal of this study was to investigate the role of PERK in ischemia-induced retinopathy using a mouse model of oxygen-induced retinopathy (OIR).

Methods : OIR was induced by exposing neonatal pups to 70% oxygen at postnatal day 7 (P7) followed by room air exposure from P12 to P17. GSK2606414 was orally administrated to pups. Western blot, immunohistochemistry and quantitative PCR (qPCR) were used to assess PERK phosphorylation, retinal changes and signaling pathways in relation to PERK inhibition.

Results : PERK phosphorylation was prominently increased in OIR retinas, which was inhibited by GSK2606414. Concomitantly, PERK inhibition significantly reduced retinal NV and RGC loss, restored astrocyte network, and promoted revascularization. Furthermore, PERK inhibition downregulated the recruitment/proliferation of macrophage/microglia but did not affect OIR-upregulated canonical angiogenic pathways.

Conclusions : Our results demonstrate that PERK is involved in ischemia-induced retinopathy and its inhibitor GSK2606414 could be a potential therapeutic agent to alleviate retinal NV and preserve neurons in the disease.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.