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Zhenhua Xu, Matthew Hartsock, Junsong Gong, Yanhong Wei, Shuang Wang, Elia J Duh; The neuroprotective role of Nrf2 in ischemia-reperfusion mouse model. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1906.
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Nrf2 is known to play a protective role in regulating oxidative stress and inflammation. Our group previously found that Nrf2 plays a cytoprotective role in murine models of retinal ischemia-reperfusion and diabetic retinopathy. The objective of this study was to explore the potential neuroprotective role of Nrf2 in the mouse ischemia-reperfusion model.
Retinal ischemia-reperfusion model was performed by elevating intraocular pressure to 90mmHg for 90 min. NeuN immunostaining of retina flat-mount and H/E staining of paraffin-embedded sections were used to determine cell loss in the ganglion cell layer. RGC-5 cells, a retinal neuronal cell line, were treated with different doses of Tert-Butyl hydroperoxide (TBH), and the level of reactive oxygen species (ROS) was measured by DCF assay. Keap1 siRNA was used to up-regulate Nrf2 activity in RGC-5 cells. The synthetic triterpenoid CDDO-Im (2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide) was used to activate Nrf2 expression in RGC-5 cells.
In the retinal ischemia-reperfusion mouse model, cell loss in ganglion cell layer was much more severe in Nrf2 knockout mice than in wild-type mice at 2 and 7 days after I/R. There was significantly more apoptosis in Nrf2 KO retinas compared to wild-type. Treatment with TBH increased ROS level in RGC-5 cells. siRNA-mediated knockdown of the Nrf2 inhibitor Keap1 exacerbated this TBH-induced ROS increase. Pharmacologic activation of Nrf2 using the triterpenoid CDDO-Im inhibited TBH-induced ROS increase in a dose-dependent fashion.
These results indicate that Nrf2 exhibits a neuronal protective function in the retinal ischemia-reperfusion model and suggest that pharmacologic activation of Nrf2 could be a therapeutic strategy.
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