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P. Malone, M. Hernandez; 4–Hydroxynonenal, a Product of Oxidative Stress, Leads to an Antioxidant Response in Optic Nerve Head Astrocytes . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1256.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the effects of oxidative stress using 4–hydroxynonenal (HNE) on human optic nerve head (ONH) astrocytes. Oxidative stress is a component of several neurodegenerative diseases, including glaucoma. HNE is a stable and highly reactive aldehyde that results from lipid peroxidation induced by oxidative stress.
ONH astrocytes from normal donors were treated with 25uM HNE for 1–3 h. cFOS, NFkB, and nuclear transcription factor erythroid 2–related factor 2 (NRF2) protein levels were measured by Western blot. Aldo–keto reductase 1C family member 1 (AKR1C1), cFOS, glutamate–cysteine ligase–catalytic subunit (GCLC), NFkB and NRF2 mRNA levels were analyzed by quantitative real–time RT–PCR. Immunocytochemistry was used to investigate nuclear translocation of cFOS. Glutathione (GSH) levels were measured with a GSH assay following HNE treatment.
ONH astrocytes exposed to HNE exhibited increased mRNA levels of AKR1C1, cFOS, GCLC, and NRF2. HNE induced nuclear translocation of cFOS and NFkB, as detected by immunocytochemistry and Western blot. HNE depleted levels of GSH in ONH astrocytes immediately after treatment as detected by a GSH assay.
ONH astrocytes respond to HNE by the activation of cFOS and NFkB transcription factors. Following HNE treatment, ONH astrocytes also upregulate enzymes that inactivate HNE, including AKR1C1. Upregulation of the transcription factor NRF2 may further upregulate other detoxification enzymes and antioxidant proteins. GSH binds covalently to HNE in order to remove HNE from the cell. Astrocytes treated with HNE showed decreased cellular levels of GSH. Lower levels of GSH then induce the expression of GCLC, the rate–limiting enzyme involved in the de novo production of GSH. Oxidative stress leads to the production of reactive oxygen species which can induce lipid peroxidation that generate the toxic aldehyde HNE. Oxidative stress has been identified as a component of the pathogenesis of glaucoma. Astrocytes may offer neuroprotection in the CNS by releasing glutathione and antioxidant enzymes to eliminate products of oxidative stress that may contribute to the progression of neurodegeneration.
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