Low-Luminance Blue Light-Enhanced Phototoxicity in A2E-Laden RPE Cell Cultures and Rats.

Lin Lin,Chow Chow,Hsiao Hsiao,Wu Wu,Cheng Cheng,Huang Huang

doi:10.3390/ijms20071799

Abstract

N-retinylidene-N-retinylethanolamine (A2E) and other bisretinoids are components of lipofuscin and accumulate in retinal pigment epithelial (RPE) cells—these adducts are recognized in the pathogenesis of retinal degeneration. Further, blue light-emitting diode (LED) light (BLL)-induced retinal toxicity plays an important role in retinal degeneration. Here, we demonstrate that low-luminance BLL enhances phototoxicity in A2E-laden RPE cells and rats. RPE cells were subjected to synthetic A2E, and the effects of BLL on activation of apoptotic biomarkers were examined by measuring the levels of cleaved caspase-3. BLL modulates the protein expression of zonula-occludens 1 (ZO-1) and paracellular permeability in A2E-laden RPE cells. Early inflammatory and angiogenic genes were also screened after short-term BLL exposure. In this study, we developed a rat model for A2E treatment with or without BLL exposure for 21 days. BLL exposure caused fundus damage, decreased total retinal thickness, and caused neuron transduction injury in the retina, which were consistent with the in vitro data. We suggest that the synergistic effects of BLL and A2E accumulation in the retina increase the risk of retinal degeneration. These outcomes help elucidate the associations between BLL/A2E and angiogenic/apoptotic mechanisms, as well as furthering therapeutic strategies.

Highlights

Abnormal regeneration of the visual retinoid chromophores—between photoreceptor cells and retinal pigment epithelial (RPE) cells—non-enzymatically forms lipofuscin, thereby threatening the survival of retinal cells
Using a long-term low-luminance periodic blue light-emitting diode (LED) light (BLL) exposure model in brown Norway (BN) rats, we demonstrate that co-treatment with A2E and BLL causes more severe retinal damage and neuronal transmission dysfunction than A2E treatment alone
Immunofluorescence staining showed an increase in discontinued or intermittent zonula-occludens 1 (ZO-1)-positive strands displaying intercellular gaps in A2E-laden RPE cells exposed to BLL for 12 h (Figure 3Co, yellow arrows), indicating that the tight junction structure was damaged

Summary

Introduction

Abnormal regeneration of the visual retinoid (retinaldehyde) chromophores—between photoreceptor cells and retinal pigment epithelial (RPE) cells—non-enzymatically forms lipofuscin, thereby threatening the survival of retinal cells. These chromophores are involved in the pathogenesis of retinal degenerative diseases such as age-related macular degeneration (AMD) and Stargardt’s disease (STGD) [1,2]. RPE cells form an epithelial monolayer located in the retina and have many functions, including absorption of light, ionic exchange, visual cycle, transportation of nutrients and wastes, phagocytosis of shed photoreceptors, as well as metabolism and immune responses [5]. RPE injury and cell death leads to secondary degeneration of photoreceptors, which characterizes advanced dry-AMD, known as geographic atrophy [7,8]

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