Involvement of XBP1s in Blue Light-Induced A2E-Containing Retinal Pigment Epithelium Cell Death

Abstract

Purpose: Retinal pigment epithelium (RPE) cell dysfunction is essential to the development of retinal degenerative disease. This study was designed to investigate how spliced X-box-binding protein 1 (XBP1s) regulates different modes of RPE cell death in vitro. Methods: Human ARPE19 cells were incubated with 25 μ<smlcap>M</smlcap> N-retinylidene-N-retinylethanolamine (A2E) and irradiated with blue light. Expressions of glucose-regulated protein 78 (GRP78) and XBP1s were detected by real-time quantitative PCR and Western blot. STF-083010 was used to suppress XBP1s expression. ARPE19 cell apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling and flow cytometry. Receptor-interacting protein kinase-3 (RIP3) was detected by Western blot. Changes in the morphology of ARPE19 cells were identified by transmission electron microscopy. Results: Blue light-induced A2E-containing ARPE19 cell damage caused a transient elevation of GRP78 and XBP1s, while RIP3 rose in the late stage. STF-083010 effectively inhibited XBP1s expression and brought about the aggravation of apoptosis together with an alleviation of RIP3 expression. Most of the dying cells exhibited apoptotic morphology. Conclusion: A2E, along with blue light, brought about apoptosis and necroptosis of ARPE19 cells, and XBP1s was transiently elevated. The suppression of XBP1s induced ARPE19 cell death by promoting apoptosis rather than necroptosis. XBP1s might play a role in the pathogenesis of retinal degenerative diseases.

Protective Effects and Molecular Signaling of n-3 Fatty Acids on Oxidative Stress and Inflammation in Retinal Diseases

“…Furthermore, sunlight exposure is a significant risk for AMD [ 196 ]. Indeed, RPE cells are particularly susceptible to wavelengths within the blue region of the solar spectrum and blue light is the most energetic radiation reaching the macula, resulting in RPE cell apoptosis and necrosis [ 197 , 198 , 199 ].…”

Fundus autofluorescence, spectral‐domain optical coherence tomography, and histology correlations in a Stargardt disease mouse model

“…A2E was proven to be an initiator in the process of blue light‐induced apoptosis and necroptosis of RPE cells . Upon exposure to blue light, A2E and iso‐A2E generate reactive oxygen species (ROS), which directly damage cells .…”

“…11,12 A2E was proven to be an initiator in the process of blue light-induced apoptosis and necroptosis of RPE cells. 13,14 Upon exposure to blue light, A2E and iso-A2E generate reactive oxygen species (ROS), which directly damage cells. 15 Photo-oxidation of bisretinoids in RPE cells is known to damage DNA of RPE cells in the presence of A2E epoxides and oxiranes, 16,17 activating the complement system and altering the transcription of genes for the stress response, apoptosis, and immune response.…”

The Effect of A2E on the Uptake and Release of Calcium in the Lysosomes and Mitochondria of Human RPE Cells Exposed to Blue Light

“…Under this condition, there were more apoptotic cells and fewer necrotic cells. e optimal concentration of A2E was determined to be 25 µM [11,12]. e cell viability significantly decreased in an A2Edose-dependent manner, and cell viability was best under this condition.…”