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Yanhong Wei, Junsong Gong, Elia J Duh; Activation of Nrf2 suppresses inflammation and semaphorin 6A signaling in oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2448. doi: https://doi.org/.
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Nrf2 acts as a master regulatory factor with cytoprotective antioxidant and anti-inflammatory properties. We have found that Nrf2 plays a protective role in retinal ischemia-reperfusion injury, diabetic retinopathy and oxygen-induced retinopathy (OIR). In a recent study, we demonstrated that Nrf2 promotes reparative angiogenesis via modulation of NADPH oxidase-2 (NOX2) in OIR. The objective of this study was to gain insights into the mechanism by which pharmacologic activation of Nrf2 promotes revascularization in OIR.
Mice were subjected to 75% oxygen from postnatal day 7 (P7) to 12, followed by return to room air. Mice received intravitreal injection with 1 μL 24 nM CDDO-Im at P12 and P14. The human Müller cell line MIO-M1 was pretreated with CDDO-Im for 18h, followed by stimulation with Lipopolysaccharide (LPS). Quantitative RT-PCR was used to assess mRNA expression. Human retinal endothelial cells (HREC) were transfected with siRNA for 24 hours and then seeded on collagen for tube formation assay.
Pharmacologic Nrf2 activation by CDDO-Im increased revascularization and suppressed pathologic neovascularization at OIR P17. CDDO-Im treatment induced Nrf2 target gene expression while suppressing NOX2 and inflammatory cytokines. Pretreatment with CDDO-Im suppressed LPS-induced IL-1β, CCL2, and ICAM1 mRNA levels in a dose-dependent fashion in MIO-M1 cells. Retinas from mice treated with CDDO-Im exhibited decreased Sema6A mRNA levels. Plexin A2 (PlxnA2), a receptor for Sema6A, was detected in retinal blood vessels in OIR. Extracellular Sema6A treatment resulted in decreased HREC tube formation, and this effect was abrogated by siRNA-mediated knockdown of PlxnA2.
These studies suggest that activation of Nrf2 suppresses inflammation and Sema6A/PlxnA2 signaling, which may play a key role in mediating enhanced revascularization by CDDO-Im treatment in OIR.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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