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Astroglial NF‐κB mediates oxidative stress by regulation of NADPH oxidase in a model of retinal ischemia reperfusion injury
Author(s) -
Barakat David J.,
Dvoriantchikova Galina,
Ivanov Dmitry,
Shestopalov Valery I.
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07595.x
Subject(s) - nadph oxidase , oxidative stress , reactive oxygen species , microbiology and biotechnology , retinal , retinal ganglion cell , astrocyte , biology , nf κb , retina , chemistry , biochemistry , signal transduction , endocrinology , neuroscience , central nervous system
J. Neurochem. (2012) 120 , 586–597. 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.