1. Nrf2 protects human lens epithelial cells against H 2 O 2 -induced oxidative and ER stress: The ATF4 may be involved.
- Author
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Ma TJ, Lan DH, He SZ, Ye Z, Li P, Zhai W, Chen WQ, Huang Y, Fu Y, Sun A, Wang YB, Ye Z, Li JL, Gao Y, Yan XL, and Li ZH
- Subjects
- Blotting, Western, Catalase metabolism, Cell Line, Cytoprotection, Epithelial Cells metabolism, Flow Cytometry, Fluorescent Antibody Technique, Indirect, Glutathione metabolism, Humans, Hydrogen Peroxide toxicity, Lens, Crystalline metabolism, Oxidants toxicity, Phosphorylation, Reactive Oxygen Species metabolism, Real-Time Polymerase Chain Reaction, Superoxide Dismutase metabolism, Transfection, Unfolded Protein Response physiology, eIF-2 Kinase metabolism, Activating Transcription Factor 4 metabolism, Endoplasmic Reticulum Stress, Epithelial Cells cytology, Lens, Crystalline cytology, NF-E2-Related Factor 2 physiology, Oxidative Stress
- Abstract
Our previous study has shown heme oxygenase-1 (HO-1) protects human lens epithelial cells (LECs) against H
2 O2 -induced oxidative stress and apoptosis. Nrf2, the major regulator of HO-1, is triggered during the mutual induction of oxidative stress and ER stress. In response to ER stress, unfolded protein response (UPR) serves as a program of transcriptional and translational regulation mechanism with PERK involved. Both Nrf2 and ATF4 are activated as the downstream effect of PERK signaling coordinating the convergence of dual stresses. However, the ways in which Nrf2 interacting with ATF4 regulates deteriorated redox state have not yet been fully explored. Here, the transfected LECs with Nrf2 overexpression illustrated enhanced resistance in morphology and viability upon H2 O2 treatment condition. Intracellular ROS accumulation arouses ER stress, initiating PERK dependent UPR and inducing the downstream signal Nrf2 and ATF4 auto-phosphorylation. Further, converging at target promoters, ATF4 facilitates Nrf2 with the expression of ARE-dependent phase II antioxidant and detoxification enzymes. According to either Nrf2 or ATF4 gene modification, our data suggests a novel interaction between Nrf2 and ATF4 under oxidative and ER stress, thus drives specific enzymatic and non-enzymatic reactions of antioxidant mechanisms maintaining redox homeostasis. Therapies that restoring Nrf2 or ATF4 expression might help to postpone LECs aging and age-related cataract formation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
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