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Yanhong Wei, Junsong Gong, Zhenhua Xu, Rajesh Thimmulappa, Shyam Biswal, Elia Duh; Nrf2 Modulates Retinal Revascularization And Pathologic Angiogenesis In Oxygen-induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2552.
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The oxygen-induced retinopathy (OIR) model has yielded significant insights into the regulation of physiologic retinal revascularization, but much remains unknown regarding molecules that promotes revascularization in this condition. Nrf2 has a well-known cytoprotective role in many tissues including the retina. The purpose of this study is to investigate the possible role of Nrf2 in oxygen-induced retinopathy using Nrf2-deficient mice.
Nrf2 knockout mice (Nrf2-/-) and corresponding wild-type control mice were subjected 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. Nrf2 translocation was evaluated beginning at various time-points by immunoblotting of nuclear and cytosolic retinal extracts. GSH levels were measured from P12 to P17. Real-time PCR was used to evaluate expression of multiple pro-inflammatory genes. The aortic ring assay, using segments from knockout and wild-type mice, was employed as a complementary approach to assess vascularization.
Nrf2 knockout mice exhibited significantly increased avascular retina and pathologic retinal neovascularization at P17 compared to wild-type. Nrf2 translocation in wild-type mice was detected as early as P12 + 2 hours. GSH levels were initially reduced in both wild-type and knockout mice. GSH levels were eventually replenished in wild-type but not knockout mice. Nrf2 knockout mice exhibited accentuation of pro-inflammatory gene expression, including IL-1β. Similar to OIR retinas, aortic ring segments from Nrf2 knockout mice exhibited decreased vascularization compared to wild-type.
These studies indicate that Nrf2 is an important modulator of retinal revascularization and pathologic neovascularization in oxygen-induced retinopathy, regulating both oxidative stress and pro-inflammatory gene expression.
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