Inhibition of oxidative stress-induced epithelial-mesenchymal transition in retinal pigment epithelial cells of age-related macular degeneration model by suppressing ERK activation

Ya-Chi Yang; Yueh Chien; Aliaksandr A. Yarmishyn; Lee-Yieng Lim; Hao-Yu Tsai; Wen-Chuan Kuo; Ping-Hsing Tsai; Sheng-Hsien Yang; Shao-I Hong; Shih-Jen Chen; De-Kuang Hwang; Yi-Ping Yang; Shih-Hwa Chiou

Journal of Advanced Research (Jun 2024)

Inhibition of oxidative stress-induced epithelial-mesenchymal transition in retinal pigment epithelial cells of age-related macular degeneration model by suppressing ERK activation

Ya-Chi Yang,
Yueh Chien,
Aliaksandr A. Yarmishyn,
Lee-Yieng Lim,
Hao-Yu Tsai,
Wen-Chuan Kuo,
Ping-Hsing Tsai,
Sheng-Hsien Yang,
Shao-I Hong,
Shih-Jen Chen,
De-Kuang Hwang,
Yi-Ping Yang,
Shih-Hwa Chiou

Affiliations

Ya-Chi Yang: Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
Yueh Chien: Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
Aliaksandr A. Yarmishyn: Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
Lee-Yieng Lim: Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan
Hao-Yu Tsai: Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
Wen-Chuan Kuo: Institute of Biophotonics, College of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
Ping-Hsing Tsai: Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
Sheng-Hsien Yang: Institute of Biophotonics, College of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
Shao-I Hong: Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
Shih-Jen Chen: College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
De-Kuang Hwang: College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
Yi-Ping Yang: Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Corresponding authors at: Department of Medical Research, Taipei Veterans General Hospital, No. 201, Sec. 2 Shipai Rd. Beitou Dist., Taipei 112201, Taiwan.
Shih-Hwa Chiou: Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan; College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan; Genomic Research Center, Academia Sinica, Taipei 115024, Taiwan; Corresponding authors at: Department of Medical Research, Taipei Veterans General Hospital, No. 201, Sec. 2 Shipai Rd. Beitou Dist., Taipei 112201, Taiwan.

Journal volume & issue: Vol. 60
pp. 141 – 157

Abstract

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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 (NaIO3) 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.

Published in Journal of Advanced Research

ISSN: 2090-1232 (Print); 2090-1224 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Science (General)
Website: http://www.journals.elsevier.com/journal-of-advanced-research/

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