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E. C. Johnson, T. A. Doser, W. O. Cepurna, J. A. Dyck, Y. Guo, J. C. Morrison; Optic Nerve Head Injury in a Rat Glaucoma Model: How Does Aging Alter Gene Expression?. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4059. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Elevated intraocular pressure (IOP) and aging are predominant risk factors for glaucoma and the optic nerve head (ONH) is the principal site of initial injury. Previously, using a rat glaucoma model, we showed that elevated IOP produces more injury in 28-month-old (28-mo) than in comparable 8-month-old (8-mo) optic nerves. Here, we use microarray analysis to compare pressure-induced gene expression changes between 8-mo and 28-mo ONH to determine if altered gene response patterns are associated with the increased susceptibility of the aged nerve.
RNA was obtained from 28-mo ONH following unilateral hypertonic saline injection to elevate IOP and fellow ONH (6 per group). Injected eyes were matched for extensive, ongoing axonal degeneration in retrobulbar optic nerves. Samples were independently evaluated using cDNA microarrays. SAM and DAVID analyses were used to identify significant differences in gene expression and affected gene categories between groups. These differences in gene expression in 28-mo ONH were compared to those found previously in 8-mo ONH in the same experimental paradigm.
Of 564 genes altered in expression by elevated IOP in the 28-mo ONH, 149 were up- and 415 downregulated. This corresponds, in number, to 10% of the up- and 48% of the downregulated genes found in the 8-mo ONH study. For the 268 regulated genes in common in the two studies, 95% were regulated in the same direction. However, for 28-mo ONH, the magnitude of change was about 50% less for some of the most dramatically upregulated genes (periostin, complement components 1q alpha and gamma, and CD34 antigen) while the expression of peptidase inhibitor, nexin-1, increased 2 fold. The biological processes and cell components of cell adhesion, cell proliferation, and extracellular matrix were similarly upregulated in 8-mo and 28-mo ONH, while immune response, protein biosynthesis, ribosome biogenesis, lysosome and Golgi apparatus categories were not. In addition to the downregulation of lipid metabolism, cytoskeleton and glutathione transferases previously identified in 8-mo ONH, 28-mo ONH also downregulated cell to cell signaling and MAPK pathway activity regulation.
Gene expression responses to elevated IOP were similar, but less dramatic in the 28-mo ONH. In particular, aging attenuated the upregulation of immune and protein biosynthetic, processing, and degradation responses. These less robust reactions to pressure insult may contribute to the increased susceptibility of the aged optic nerve to glaucomatous axon loss.
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