Temporary Upregulation of Nrf2 by Naringenin Alleviates Oxidative Damage in the Retina and ARPE-19 Cells.

Wenpei Chen,Junli Lin,Wei Yang,Zhongrui Wu,Yiting Wang,Bingqing Lin,Xinrong Yang,Qi Ding,Yuxin Ye,Baoqin Lin,Daniel Lopez Malo

doi:10.1155/2021/4053276

Abstract

Dry age-related macular degeneration (dAMD) is a chronic degenerative ophthalmopathy that leads to serious burden of visual impairment. Antioxidation in retinal pigment epithelium (RPE) cells is considered as a potential treatment for dAMD. Our previous studies have showed that naringenin (NAR) protects RPE cells from oxidative damage partly through SIRT1-mediated antioxidation. In this study, we tested the hypothesis that the Nrf2 signaling is another protective mechanism of NAR on dAMD. NaIO3-induced mouse retinopathy and ARPE-19 cell injury models were established. Immunochemical staining, immunofluorescence, and western blotting were performed to detect the protein expressions of Nrf2 and HO-1. In addition, ML385 (activity inhibitor of Nrf2) and zinc protoporphyrin (ZnPP, activity inhibitor of HO-1) were applied to explore the effect of NaIO3 or NAR. The results showed that NAR increased the protein expressions of Nrf2 and HO-1 in the retinas in mice exposed to NaIO3 at the early stage. NAR treatment also resulted in a stronger activation of Nrf2 at the early stage in NaIO3-treated ARPE-19 cells. Moreover, inhibition of HO-1 by ZnPP weakened the cytoprotective effect of NAR. The constitutive accumulation and activation of Nrf2 induced by NaIO3 led to the death of RPE cells. However, NAR decreased the protein expressions of Nrf2 and HO-1 towards normal level in the mouse retinas and ARPE-19 cells exposed to NaIO3 at the late stage. Our findings indicate that NAR protects RPE cells from oxidative damage via activating the Nrf2 signaling pathway.

Highlights

Age-related macular degeneration (AMD) is a progressive chronic ophthalmopathy with aging and eventually results in serious visual impairment
In this study, we investigated whether Nuclear factor erythroid 2-related factor 2 (Nrf2)/HO1-mediated antioxidant mechanism was involved in the protective effect of NAR in NaIO3-treated mice in vivo and ARPE-19 cells in vitro
After NaIO3 stimulation, Nrf2 and HO-1 proteins were increased in the ganglion cell layer (GCL), inner plexiform layer (IPL), outer plexiform layer (OPL), photoreceptor inner segment (PIS), and especially photoreceptor outer segment (POS) and retinal pigment epithelium (RPE)

Summary

Introduction

Age-related macular degeneration (AMD) is a progressive chronic ophthalmopathy with aging and eventually results in serious visual impairment. Oxidative stress is considered as a central contributor to the progress of dAMD. Prooxidative factors such as aging, smoking, and sunlight lead to the oxidative insult in RPE cells, manifesting as the formation of deposit and drusen between the RPE and Bruch membrane (BrM). Besides causing the death of RPE, oxidative stress compels RPE to detach from BrM and makes RPE losing function. The death and dysfunction of RPE result in poor nutrient supply of photoreceptors, which causes the atrophy of photoreceptors gradually [2]. Antioxidation targeting to RPE cells is a potential treatment for dAMD

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