1. Inhibition of oxidative stress-induced epithelial-mesenchymal transition in retinal pigment epithelial cells of age-related macular degeneration model by suppressing ERK activation.
- Author
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Yang YC, Chien Y, Yarmishyn AA, Lim LY, Tsai HY, Kuo WC, Tsai PH, Yang SH, Hong SI, Chen SJ, Hwang DK, Yang YP, and Chiou SH
- Subjects
- Animals, Humans, Mice, Cell Line, Extracellular Signal-Regulated MAP Kinases metabolism, MAP Kinase Signaling System drug effects, Mice, Inbred C57BL, Signal Transduction drug effects, ErbB Receptors metabolism, Epithelial Cells metabolism, Epithelial Cells drug effects, Retinal Pigment Epithelium metabolism, Macular Degeneration metabolism, Macular Degeneration drug therapy, Oxidative Stress drug effects, Epithelial-Mesenchymal Transition drug effects, Iodates, Reactive Oxygen Species metabolism, Disease Models, Animal
- Abstract
Introduction: Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is related to the pathogenesis of various retinopathies including age-related macular degeneration (AMD). Oxidative stress is the major factor that induces degeneration of RPE cells associated with the etiology of AMD., Objectives: Sodium iodate (NaIO
3 ) generates intracellular reactive oxygen species (ROS) and is widely used to establish a model of AMD due to the selective induction of retinal degeneration. This study was performed to clarify the effects of multiple NaIO3 -stimulated signaling pathways on EMT in RPE cells., Methods: The EMT characteristics in NaIO3 -treated human ARPE-19 cells and RPE cells of the mouse eyes were analyzed. Multiple oxidative stress-induced modulators were investigated and the effects of pre-treatment with Ca2+ chelator, extracellular signal-related kinase (ERK) inhibitor, or epidermal growth factor receptor (EGFR) inhibitor on NaIO3 -induced EMT were determined. The efficacy of post-treatment with ERK inhibitor on the regulation of NaIO3 -induced signaling pathways was dissected and its role in retinal thickness and morphology was evaluated by using histological cross-sections and spectral domain optical coherence tomography., Results: We found that NaIO3 induced EMT in ARPE-19 cells and in RPE cells of the mouse eyes. The intracellular ROS, Ca2+ , endoplasmic reticulum (ER) stress marker, phospho-ERK, and phospho-EGFR were increased in NaIO3 -stimulated cells. Our results showed that pre-treatment with Ca2+ chelator, ERK inhibitor, or EGFR inhibitor decreased NaIO3 -induced EMT, interestingly, the inhibition of ERK displayed the most prominent effect. Furthermore, post-treatment with FR180204, a specific ERK inhibitor, reduced intracellular ROS and Ca2+ levels, downregulated phospho-EGFR and ER stress marker, attenuated EMT of RPE cells, and prevented structural disorder of the retina induced by NaIO3 ., Conclusions: ERK is a crucial regulator of multiple NaIO3 -induced signaling pathways that coordinate EMT program in RPE cells. Inhibition of ERK may be a potential therapeutic strategy for the treatment of AMD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)- Published
- 2024
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