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T. A. Doser, J. A. Dyck, W. O. Cepurna, Y. Guo, J. C. Morrison, E. C. Johnson; A Comparison of Intraocular Pressure Elevation and Optic Nerve Transection on Optic Nerve Head Gene Expression Reveals Unique Pressure-Induced Responses. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3696.
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© ARVO (1962-2015); The Authors (2016-present)
Using a rat glaucoma model, we have demonstrated that elevated intraocular pressure (IOP) results in dramatic alterations in optic nerve head (ONH) gene expression that are correlated with initial injury and/or accumulating axon loss. In this study, we use optic nerve transection (ONT) to produce axon loss and ONH reorganziation unrelated to pressure, to determine the specific, pressure-related patterns of ONH gene response.
Gene expression was determined in the anterior, 0.4 mm (scleral) ONH using microarray analysis and quantitative RT-PCR (qPCR). For microarrays, experimental groups were (1) glaucoma model ONH from eyes with extensive, ongoing retrobulbar optic nerve degeneration, (2) ONH at 14 days following distal, intraorbital optic nerve transection and (3) controls (N=6 per group, 18 arrays). SAM multiclass analysis, ANOVA with post tests and DAVID (NIAID) were used to determine significant differences. In addition, expression patterns of selected genes were determined by qPCR in 50 glaucoma model ONH with various degrees of optic nerve injury and ONH at 1, 7 and 14 days following transection (N≥7 per group).
Elevated IOP and ONT resulted in changed expression of 962 and 594 genes in the ONH, respectively. Of these, 526 were altered in the same direction by both injuries. In addition, 392 genes (219 up- and 173 downregulated) were found to be selectively altered by elevated IOP, compared to both ONT and control values. Pressure alone upregulated the biological processes of cell adhesion and protein biosynthesis, including ribosomal, transmembrane receptor, membrane and extracellular proteins, while downregulating RNA splicing, cytoskeletal proteins and hedgehog receptor activity. qPRC studies demonstrated that elevated IOP resulted in unique upregulation of adrenomedullin and proliferating cell nuclear antigen. In addition, pressure-exposure significantly enhanced the upregulation of fibulin 2, interleukin 6, matrix gla protein, periostin, ADAMTS1 and topoisomerase 2a to levels that were 2 to 6 times the maximum values seen following ONT.
This study identifies specific effects of IOP elevation on ONH gene expression by separating them from epiphenomena resulting from the process of axon degeneration. Pressure-induced injury results in an overall upregulation of protein biosynthetic processes, specifically affects certain gene classes, produces more dramatic responses in functionally diverse message levels and uniquely regulates specific genes.
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