Involvement of Endoplasmic Reticulum Stress in All-Trans-Retinal-Induced Retinal Pigment Epithelium Degeneration
| Autor: | Yanli Zhang, Hua Naranmandura, Jie Li, Ke Yao, Xianhui Cai, Yalin Wu, Xin Liu, Jingmeng Chen, Qingqing Xia |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Apoptosis
Tretinoin Retinal Pigment Epithelium Mitochondrion Biology Endoplasmic Reticulum Toxicology medicine.disease_cause Antioxidants Cell Line Salubrinal chemistry.chemical_compound medicine Humans Membrane Potential Mitochondrial chemistry.chemical_classification Reactive oxygen species Retinal pigment epithelium Dose-Response Relationship Drug Endoplasmic reticulum Retinal Endoplasmic Reticulum Stress eye diseases Mitochondria Cell biology Oxidative Stress medicine.anatomical_structure Gene Expression Regulation chemistry Cytoprotection Unfolded protein response sense organs Apoptosis Regulatory Proteins Reactive Oxygen Species Oxidative stress Signal Transduction |
| Zdroj: | Toxicological Sciences. 143:196-208 |
| ISSN: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kfu223 |
| Popis: | Excess accumulation of endogenous all-trans-retinal (atRAL) contributes to degeneration of the retinal pigment epithelium(RPE) and photoreceptor cells, and plays a role in the etiologies of age-related macular degeneration (AMD) and Stargardt’sdisease. In this study, we reveal that human RPE cells tolerate exposure of up to 5mM atRAL without deleterious effects, buthigher concentrations are detrimental and induce cell apoptosis. atRAL treatment significantly increased production ofintracellular reactive oxygen species (ROS) and up-regulated mRNA expression of Nrf2, HO-1, and c-GCSh within RPE cells,thereby causing oxidative stress. ROS localized to mitochondria and endoplasmic reticulum (ER). ER-resident molecularchaperone BiP, a marker of ER stress, was up-regulated at the translational level, and meanwhile, the PERK-eIF2a-ATF4signaling pathway was activated. Expression levels of ATF4, CHOP, and GADD34 in RPE cells increased in a concentration-dependent manner after incubation with atRAL. Salubrinal, a selective inhibitor of ER stress, alleviated atRAL-induced celldeath. The antioxidant N-acetylcysteine (NAC) effectively blocked RPE cell loss and ER stress activation, suggesting thatatRAL-induced ROS generation is responsible for RPE degeneration and is an early trigger of ER stress. Furthermore, themitochondrial transmembrane potential was lost after atRAL exposure, and was followed by caspase-3 activation and poly(ADP-ribose) polymerase cleavage. The results demonstrate that atRAL-driven ROS overproduction-induced ER stress isinvolved in cellular mitochondrial dysfunction and apoptosis of RPE cells.Key words: all-trans-retinal; retinal pigment epithelium; endoplasmic reticulum; reactive oxygen species; mitochondrialdysfunction. |
| Databáze: | OpenAIRE |
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