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

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.

SUBMITTER: Lin CH

PROVIDER: S-EPMC6480556 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Lin Cheng-Hui CH Wu Man-Ru MR Huang Wei-Jan WJ Chow Diana Shu-Lian DS Hsiao George G Cheng Yu-Wen YW

International journal of molecular sciences 20190411 7

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 ...[more]

PMID: 30979028

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Project description:Natural products with significant antioxidant activity have been receiving attention as one of the treatment strategies to prevent age-related macular degeneration (AMD). Reactive oxygen intermediates (ROI) including oxo-N-retinylidene-N-retinylethanolamine (oxo-A2E) and singlet oxygen-induced damage, are believed to be one of the major causes of the development of AMD. To investigate the therapeutic effects of methanol extracts of Dipterocarpus tuberculatus Roxb. (MED) against blue light (BL)-caused macular degeneration, alterations in the antioxidant activity, apoptosis pathway, neovascularization, inflammatory response, and retinal degeneration were analyzed in A2E-laden ARPE19 cells and Balb/c mice after exposure of BL. Seven bioactive components, including 2α-hydroxyursolic acid, ε-viniferin, asiatic acid, bergenin, ellagic acid, gallic acid and oleanolic acid, were detected in MED. MED exhibited high DPPH and ABTS free radical scavenging activity. BL-induced increases in intracellular reactive oxygen species (ROS) production and nitric oxide (NO) concentration were suppressed by MED treatment. A significant recovery of antioxidant capacity by an increase in superoxide dismutase enzyme (SOD) activity, SOD expression levels, and nuclear factor erythroid 2-related factor 2 (NRF2) expression were detected as results of MED treatment effects. The activation of the apoptosis pathway, the expression of neovascular proteins, cyclooxygenase-2 (COX-2)-induced inducible nitric oxide synthase (iNOS) mediated pathway, inflammasome activation, and expression of inflammatory cytokines was remarkably inhibited in the MED treated group compared to the Vehicle-treated group in the AMD cell model. Furthermore, MED displayed protective effects in BL-induced retinal degeneration through improvement in the thickness of the whole retina, outer nuclear layer (ONL), inner nuclear layer (INL), and photoreceptor layer (PL) in Balb/c mice. Taken together, these results indicate that MED exhibits protective effects in BL-induced retinal degeneration and has the potential in the future to be developed as a treatment option for dry AMD with atrophy of retinal pigment epithelial (RPE) cells.

Project description:BackgroundAge-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) is closely related to the etiology of autosomal recessive Stargardt's disease (STGD1) and dry age-related macular degeneration (AMD). N-retinylidene-N-retinylethanolamine (A2E) is a leading component of RPE lipofuscin that is highly susceptible to blue light. Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by the accumulation of lipid peroxides to a lethal level, which plays an important role in retinal diseases. However, it remains unknown whether A2E functions as a physiological trigger for eliciting blue light-induced ferroptosis of RPE cells.MethodsA2E-loaded RPE cells and Abca4-/-Rdh8-/- mice were exposed to blue light, respectively. Western blotting, immunofluorescence staining, reactive oxygen species (ROS) staining, intracellular iron staining, lipid peroxidation staining, fundus imaging, optical coherence tomography (OCT), hematoxylin-eosin (HE) staining, and electroretinography (ERG) were utilized to elucidate the role of blue light in A2E induced ferroptosis in the RPE and its potential mechanisms.ResultsExposure of A2E to blue light promoted ferroptotic cell death in RPE cells by elevating ferrous ion (Fe2+) levels and inhibiting the solute carrier family 7 membrane 11 (SLC7A11)-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis. GPX4 inactivation and ROS generated by Fe2+ overload and GSH depletion precipitated lipid peroxidation and subsequent ferroptosis in A2E-containing RPE cells upon exposure to blue light. In addition to GSH supplement, repressing either Fe2+ by deferiprone (DFP) or lipid peroxidation with ferrostatin-1 (Fer-1) significantly protected RPE cells against ferroptosis caused by blue light illumination of A2E. Abca4-/-Rdh8-/- mice featured by an accelerated deposition of A2E in the RPE is an animal model for STGD1 and dry AMD. It was observed that ferroptosis was indeed present in the RPE of Abca4-/-Rdh8-/- mice following exposure to blue light. Notably, alleviating ferroptosis by intraperitoneally injected Fer-1 effectively rescued retinal function and ameliorated RPE/photoreceptor degeneration in blue light-exposed Abca4-/-Rdh8-/- mice.ConclusionsOur results suggest the importance of blue light in A2E-mediated ferroptosis in the RPE, and deeply broaden the understanding of mechanisms underlying RPE atrophy arising from lipofuscin accumulation in STGD1 and dry AMD.

Project description:Natural products with high antioxidant activity are considered as innovative prevention strategies to effectively prevent age-related macular degeneration (AMD) in the early stage because the generation of reactive oxygen species (ROS) leading to the development of drusen is reported as an important cause of this disease. To investigate the prevention effects of the methanol extracts of Euphorbia heterophylla L. (MEE) on AMD, its effects on the antioxidant activity, inflammatory response, apoptosis pathway, neovascularization, and retinal tissue degeneration were analyzed in N-retinylidene-N-retinylethanolamine (A2E)-landed spontaneously arising retinal pigment epithelia (ARPE)-19 cells and BALB/c mice after exposure to blue light (BL). The MEE contained 10 active components and showed high free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and nitric oxide (NO) radicals. The pretreatments of high-dose MEE remarkably suppressed the production of intracellular ROS (88.2%) and NO (25.2%) and enhanced (SOD) activity (84%) and the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2) in A2E + BL-treated ARPE-19 cells compared to Vehicle-treated group. The activation of the inducible nitric oxide synthase (iNOS)-induced cyclooxygenase-2 (COX-2) mediated pathway, inflammasome activation, and expression of inflammatory cytokines was significantly inhibited in A2E + BL-treated ARPE-19 cells after the MEE pretreatment. The activation of the apoptosis pathway and increased expression of neovascular proteins (36% for matrix metalloproteinase (MMP)-9) were inhibited in the MEE pretreated groups compared to the Vehicle-treated group. Furthermore, the thickness of the whole retina (31%), outer nuclear layer (ONL), inner nuclear layer (INL), and photoreceptor layer (PL) were significantly increased by the MEE pretreatment of BALB/c mice with BL-induced retinal degeneration. Therefore, these results suggest that the MEE, with its high antioxidative activity, protects against BL-induced retinal degeneration through the regulation of the antioxidative system, inflammatory response, apoptosis, and neovascularization in the AMD mouse model.

Dataset Information

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

Publications

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

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