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A. Iriyama, Y. Yanagi, Y. Inoue, H. Takahashi, Y. Tamaki; Role of A2e in the Pathogenesis of CNV . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4146.
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© ARVO (1962-2015); The Authors (2016-present)
Accumulation of fluorescent lipofuscin granules in retinal pigment epithelium (RPE) cells increases the risk of developing exudative age–related macular degeneration (AMD), the devastating condition characterized by choroidal neovascularization (CNV). Among factors that confer lipofuscin cytotoxicity, A2e is one of the best–studied components in lipofuscin. In this study, we investigated the role of A2e in the pathogenesis of CNV.
In vitro, 12, 24 and 48 hours after ARPE–19 cells, human RPE cell line, were exposed to A2e, the expression levels of VEGF, PEDF and HIF–1 was measured by ELISA and/or RT–PCR. In vivo, 7 days after A2e was injected into the subretinal space of rats, choroid/RPE was separated from the retina, and expression levels of VEGF and HIF–1 were examined by mean of RT– PCR, and RPE cell number was enumerated using choroid/RPE flat mount. Moreover, twenty–four hours after subretinal injection of A2e, CNV was induced by laser phtocoagulation in fundus of rats, and its activity was studied using fluorescein angiography (FA) 5 days thereafter. Furthermore, the effect of A2e on several nuclear receptors was examined in vitro using luciferase assay.
In ARPE19 cells, A2e treatment upregulated VEGF and HIF–1 expression and downregulated PEDF expression, both at protein and mRNA levels. In rats, expression levels of VEGF and HIF–1 were increased at mRNA level in the A2e–injected eyes and the number of RPE cells in the A2e–injected eyes was significantly decreased compared to control eyes. FA revealed that the leakage from the CNV lesion in the A2e–injected eyes was significantly increased compared to control. Luciferase assay showed that A2e treatment transactivates a retinoic acid receptor, RARα.
A2e treatment increases the expression of pro–angiogenic factors and decreases the expression of anti–angiogenic factors both in vitro and in vivo, and the CNV was more active in the A2e–injected eyes compared to control, suggesting that A2e promotes the formation and growth of CNV. This can be attributed to the activation of RARα, at least in part.
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