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Yanhong Wei, Junsong Gong, Rajesh Thimmulappa, Shyam Biswal, Elia Duh; Role of Nrf2 in the regulation of retinal revascularization and pathologic angiogenesis in oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5580.
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Nrf2 is an important regulator of the antioxidant response and also has anti-inflammatory effects. We have previously demonstrated that Nrf2 has a cytoprotective role in the retina in ischemia-reperfusion injury. The objective of this study is to gain insights into the possible role of Nrf2 in retinopathy of prematurity using the oxygen-induced retinopathy.
For studies of oxygen-induced retinopathy, mice were subjected to hyperoxia from postnatal day 7 (P7) to 12, followed by return to room air. Retinal flatmounts were prepared at P12 and P17, and analyzed for avascular retinal area as well as retinal neovascularization. For these studies, we employed global Nrf2 knockout mice (Nrf2-/-) and corresponding wild-type control mice, as well as cell-specific conditional knockout mice. Complementary studies of vascularization were performed using the aortic ring assay, using segments from knockout and wild-type mice, as well as the in vitro tube formation assay using Nrf2 knockdown.
At P12, there was no difference in the extent of retinal vaso-obliteration between Nrf2 knockout and wild-type mice. However, Nrf2 knockout mice exhibited significantly increased avascular retina and pathologic retinal neovascularization at P17 compared to wild-type. Aortic ring segments from knockout mice exhibited a marked reduction in vascularization compared to wild-type mice. Knockdown of Nrf2 by siRNA inhibited retinal endothelial tube formation. Deletion of Nrf2 in Muller cells using Nes-Cre did not affect revascularization. Deletion of Nrf2 in neuroretina (and Muller cells) using Six3-cre significantly impaired revascularization.
These studies suggest that Nrf2 could play an important role in retinopathy of prematurity and oxygen-induced retinopathy, by promoting revascularization of avascular retina, and provide insights into the cell types in which Nrf2 functions in these conditions.
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