title: Astroglial NF-κB mediates oxidative stress by regulation of NADPH oxidase in a model of retinal ischemia reperfusion injury.
abstract: Astrocytes undergo rapid activation after injury, which is mediated in part by the transcription factor nuclear factor-kappaB (NF-κB). Consequently, activated astrocytes have been shown to induce the NF-κB regulated phagocyte NADPH oxidase (PHOX), resulting in elevated production of reactive oxygen species. We investigated the regulatory mechanisms of PHOX-induced oxidative stress in astrocytes and its non-cell-autonomous effects on retinal ganglion cell loss following retinal ischemia-reperfusion (IR) injury. To study PHOX activity and neurotoxicity mediated by glial NF-κB, we employed GFAP-IκBα-dn transgenic mice, where the NF-κB canonical pathway is suppressed specifically in astrocytes. Our analysis showed that NF-κB activation in astrocytes correlated with an increased expression of PHOX and reactive oxygen species production in primary cells and whole retinas subjected to oxygen-glucose deprivation or IR injury. Selective blockade of NF-κB in astrocytes or application of NADPH oxidase inhibitors suppressed retinal ganglion cell loss in co-cultures with astroglia challenged by oxygen-glucose deprivation. Furthermore, genetic suppression of astroglial NF-κB reduced oxidative stress in ganglion layer neurons in vivo in retinal IR. Collectively, our results suggest that astroglial NF-κB-regulated PHOX activity is a crucial toxicity pathway in the pathogenesis of retinal IR injury.
authors: Department of Molecular, Cell and Developmental Biology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: David J
authors: DJ
authors: Barakat
authors: Galina
authors: G
authors: Dvoriantchikova
authors: Dmitry
authors: D
authors: Ivanov
authors: Valery I
authors: VI
authors: Shestopalov
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000378:metabolism* / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D012164:Retinal Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D019255:NADPH Oxidases