Fisetin Attenuated Oxidative Stress-Induced Cellular Damage in ARPE-19 Human Retinal Pigment Epithelial Cells Through Nrf2-Mediated Activation of Heme Oxygenase-1

Cheol Park; Jeong Sook Noh; Youngmi Jung; Sun-Hee Leem; Jin Won Hyun; Young-Chae Chang; Taeg Kyu Kwon; Gi-Young Kim; Hyesook Lee; Yung Hyun Choi

doi:10.3389/fphar.2022.927898

Fisetin Attenuated Oxidative Stress-Induced Cellular Damage in ARPE-19 Human Retinal Pigment Epithelial Cells Through Nrf2-Mediated Activation of Heme Oxygenase-1

Front Pharmacol. 2022 Jun 16:13:927898. doi: 10.3389/fphar.2022.927898. eCollection 2022.

Authors

Cheol Park¹, Jeong Sook Noh², Youngmi Jung^{3

4}, Sun-Hee Leem^{5

6}, Jin Won Hyun⁷, Young-Chae Chang⁸, Taeg Kyu Kwon⁹, Gi-Young Kim¹⁰, Hyesook Lee¹¹, Yung Hyun Choi^{12

13}

Affiliations

¹ Division of Basic Sciences, College of Liberal Studies, Dong-Eui University, Busan, South Korea.
² Department of Food Science and Nutrition, Tongmyong University, Busan, South Korea.
³ Department of Integrated Biological Science, Pusan National University, Busan, South Korea.
⁴ Department of Biological Sciences, Pusan National University, Busan, South Korea.
⁵ Department of Biomedical Sciences, Dong-A University, Busan, South Korea.
⁶ Department of Health Sciences, Dong-A University, Busan, South Korea.
⁷ Department of Biochemistry, College of Medicine, Jeju National University, Jeju, South Korea.
⁸ Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu, South Korea.
⁹ Department of Immunology, School of Medicine, Keimyung University, Daegu, South Korea.
¹⁰ Department of Marine Life Science, Jeju National University, Jeju, South Korea.
¹¹ Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, South Korea.
¹² Anti-Aging Research Center and Core-Facility Center for Tissue Regeneration, Dong-Eui University, Busan, South Korea.
¹³ Department of Biochemistry, Dong-Eui University College of Korean Medicine, Busan, South Korea.

Abstract

Fisetin is a kind of bioactive flavonol, widely present in various fruits such as strawberries and apples, and is known to act as a potent free radical scavenger. However, the mechanism of action related to the antioxidant activity of this compound in human retinal pigment epithelial (RPE) cells is not precisely known. In this study, we aimed to investigate whether fisetin could attenuate oxidative stress-induced cytotoxicity on human RPE ARPE-19 cells. To mimic oxidative stress, ARPE-19 cells were treated with hydrogen peroxide (H₂O₂), and fisetin significantly inhibited H₂O₂-induced loss of cell viability and increase of intracellular reactive oxygen species (ROS) production. Fisetin also markedly attenuated DNA damage and apoptosis in H₂O₂-treated ARPE-19 cells. Moreover, mitochondrial dysfunction in H₂O₂-treated cells was alleviated in the presence of fisetin as indicated by preservation of mitochondrial membrane potential, increase of Bcl-2/Bax expression ratio, and suppression of cytochrome c release into the cytoplasm. In addition, fisetin enhanced phosphorylation and nuclear translocation of nuclear factor erythroid 2 related factor 2 (Nrf2), which was associated with increased expression and activity of heme oxygenase-1 (HO-1). However, the HO-1 inhibitor, zinc protoporphyrin, significantly reversed the protective effect of fisetin against H₂O₂-mediated ARPE-19 cell injury. Therefore, our results suggest that Nrf2-mediated activation of antioxidant enzyme HO-1 may play an important role in the ROS scavenging activity of fisetin in RPE cells, contributing to the amelioration of oxidative stress-induced ocular disorders.

Keywords: DNA damage; Nrf2/HO-1; ROS; apoptosis; fisetin; human retinal pigment epithelial cells.