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E. C. Johnson, T. A. Doser, J. A. Dyck, Y. Guo, W. S. Lambert, W. O. Cepurna, J. C. Morrison; Early Optic Nerve Head (ONH) Astrocytic Reaction to Elevated Intraocular Pressure (IOP) is Characterized by Dedifferentiation and Proliferation. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5215.
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In glaucomatous injury, astrocytes are said to become reactive, a term usually equated with the upregulation of glial fibrillary acidic protein (Gfap) and that can imply processes that actively injure axons. Previous studies of ONH responses in our glaucoma model, however, indicate that proliferation is the dominant response to elevated IOP exposure and that Gfap is not upregulated. Here, we further characterize ONH astrocyte reactions by examining cell specific message levels and by immunolabeling proliferating cells.
Chronic IOP elevation was produced in rats by sclerosing aqueous outflow pathways with hypertonic saline. Optic nerve cross sections were graded for axon degeneration. Message levels for astrocytic marker proteins were determined using qPCR in three ONH groups: controls, early injury (<15% axon loss, N=20), and advanced injury (>15% axon loss, N=24). Ki67 antibodies were used to immunolabel dividing cells in comparable ONH groups. Statistical significance was tested by ANOVA.
For both injury groups, message levels for mature, differentiated astrocyte markers [Gfap, aquaporin 4 (Aqp4), gap junction associated protein (connexin 43, Gja1) and multiple EGF-like-domains 10 (Megf10)] were either unchanged or significantly decreased. Among markers for immature astrocytes [paired box 2 (Pax2), nestin (Nes) and vimentin (Vim)], Vim alone demonstrated a small upregulation that became significant only in advanced injury (145 ± 8%). Ki67 nuclear labeling of ONH glial column nuclei in both glaucoma groups was significantly more intense (p<0.01) than in controls.
Reactive astrocytic hypertrophy, as evidenced by increased cell marker expression, does not characterize early glaucomatous ONH injury. Rather, these data suggest that astrocytic dedifferentiation and proliferation typify initial reactions to elevated IOP exposure and imply a compromised ability to provide axonal support that may increase axonal vulnerability to injury.
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