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Yanhong Wei, junsong gong, Rajesh K. Thimmulappa, Shyam Biswal, Elia J Duh; Regulation of oxidative stress and inflammation by Nrf2 improves revascularization in oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3653.
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Nrf2 is a cytoprotective transcription factor that appears to play an important role in the regulation of stress-induced antioxidant and anti-inflammatory responses. We have previously demonstrated that Nrf2 exerts a protective effect on retinal ischemia-reperfusion injury and diabetic retinopathy. In a recent study, we found that neuronal Nrf2 enhances retinal revascularization via suppression of semaphorin 6A in oxygen-induced retinopathy (OIR). The objective of this study was to gain insights into the mechanism by which Nrf2 modulates oxidative stress and inflammation in OIR.
Nrf2 knockout (Nrf2-/-) and corresponding wild-type mice were subjected to 75% oxygen from postnatal day 7 (P7) to 12, followed by return to room air. Retinal flatmounts were stained with GS-lectin to visualize the vasculature and analyze avascular retinal area as well as retinal neovascularization. Glutathione (GSH) concentration was assessed using Glutathione Assay Kit. Superoxide anion in retina was quantified by lucigenin assay. Quantitative RT-PCR was used to assess mRNA expression.
In contrast to Nrf2-/-, the Nrf2 target gene, NQO1, was markedly induced in wild-type retina from P12 to P17. At P12 and P14, there was no difference in the extent of retinal vaso-obliteration between Nrf2-/- and wild-type mice. However, Nrf2 knockout mice exhibited significantly increased avascular retina and pathologic retinal neovascularization at P17 compared to wild-type. Nrf2-/- mice exhibited a marked decrease in GSH and an exacerbation of increase in superoxide at P15 of OIR, compared to wild-type. More pronounced upregulation of inflammatory cytokines and NOX2 was observed in Nrf2-/- at P15 of OIR. Fluorescence staining showed that NOX2 predominantly expressed in vessels and the surrounding cells.
These studies suggest that Nrf2 promotes revascularization by modulation of oxidative stress and inflammation in the retina in OIR.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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