Although excessive nitric oxide (NO) induced from iNOS is critical for dysfunction of vascular endothelial cells (ECs) in the diabetic retina, its role on ECs injury remains unknown. RPE (retinal pigment epithelium) is the pigmented cell layer just outside the neurosensory retina that constitutes the blood-retinal-barrier (BRB) with ECs, and also serves as the limiting transport factor that maintains the retinal environment. Dysfunction of the RPE is related to oxidative stress that contributes to the progression of diabetic retina. Using a co-cultural biosystem, we demonstrate that NO generation and iNOS expression was increased in both ECs and RPE cells after high glucose treatment. Increased NO in ECs cocultured with RPE activate the endoplasmic reticulum (ER) and protein kinase RNA (PKR)-like ER kinase (PERK) pathway and involved in ECs apoptosis. Blockade of the iNOS pathway, or depletion of PERK effectively, reverses NO-mediated apoptosis. Our study demonstrates that iNOS and subsequently excessive NO generation in RPE cells can have an unanticipated effect by activating PERK pathways in ECs, resulting in a novel mechanism for vascular endothelium to avoid injury from prolonged hyperglycemia.
Keywords: Apoptosis; Diabetic retina; Endothelial cells (ECs); PERK; Retinal pigment epithelium (RPE); iNOS.
Copyright © 2014 Elsevier Inc. All rights reserved.