Astroglial NF-κB mediates oxidative stress by regulation of NADPH oxidase in a model of retinal ischemia reperfusion injury

David J. Barakat, Galina Dvoriantchikova, Dmitry V Ivanov, Valery I Shestopalov

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)586-597
Number of pages12
JournalJournal of Neurochemistry
Volume120
Issue number4
DOIs
StatePublished - Feb 1 2012

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Oxidative stress
NADPH Oxidase
Reperfusion Injury
Astrocytes
Oxidative Stress
Phagocytes
Retinal Ganglion Cells
Reactive Oxygen Species
Chemical activation
Oxygen
Genetic Suppression
Glucose
Coculture Techniques
Neuroglia
Ganglia
Transgenic Mice
Neurons
Reperfusion
Toxicity
Retina

Keywords

  • astrocyte
  • ischemia
  • NADPH oxidase
  • NF-κB
  • oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Astroglial NF-κB mediates oxidative stress by regulation of NADPH oxidase in a model of retinal ischemia reperfusion injury. / Barakat, David J.; Dvoriantchikova, Galina; Ivanov, Dmitry V; Shestopalov, Valery I.

In: Journal of Neurochemistry, Vol. 120, No. 4, 01.02.2012, p. 586-597.

Research output: Contribution to journalArticle

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