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T. A. Doser, W. O. Cepurna, L. Jia, Y. Guo, J. C. Morrison, E. C. Johnson; Aging Alters Optic Nerve Head Gene Expression Responses to Elevated Intraocular Pressure in a Rat Glaucoma Model. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3277.
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As a major risk factor for glaucoma, understanding how aging affects pathogenesis of the disease is important. Previously, our microarray and RT-PCR studies have demonstrated dramatically altered gene expression in optic nerve head (ONH) of adult rats exposed to elevated intraocular pressure (IOP). In this study, we examine the effect of aging and elevated IOP on the expression of selected genes by comparing mRNA levels in aged (28 month old) and adult (8 month) rat ONH by qPCR.
Sustained unilateral IOP elevation was produced by hypertonic saline episcleral vein injection in Brown Norway Rat rats (N=38 adult and 40 aged). ONH were grouped by age and the amount of retrobulbar optic nerve injury. mRNA levels for tissue inhibitor of metalloproteinase-1 (TIMP-1), periostin, tenascin C, cyclin D1, collagen VI, fibulin 2, microglia-specific protein 1 (IBA1) and aquaporin 4 were measured by qPCR and data analyzed by 2-way ANOVA.
As in adult ONH, TIMP-1, tenascin C, cyclin D1, fibulin 2 and aquaporin 4 levels demonstrated maximal responses in aged ONH with focal optic nerve injury, while for collagen VI , IBA1 and periostin, peak levels were attained in the ONH group with the most extensive nerve injury (p<0.05). However, age had significant impact on all responses except that of aquaporin 4. For example, ONH from aged eyes with focal optic nerve injury had significantly greater levels of TIMP-1 (11.5±2.3 vs 4.3±0.7 fold, p<0.001) and fibulin 2 (7.8±1.5 vs 3.0±0.6 fold, p<0.01) mRNA than comparable adult ONH. For periostin, pressure-induced increases in the most severely injured ONH were significantly lower in the aged ONH (3.5±0.3 vs 7.45±1.5 fold, p<0.01) while IBA1 was significantly upregulated (3.3±0.3 vs. 1.5±0.1 fold, p<0.05).
In general, the gene expression response patterns to elevated IOP were similar between adult and aged ONH. This confirms previous observations that some messages are more highly expressed in ONH with focal optic nerve injury and suggests that these expression changes may be more closely related to the injury process than to glial scar formation. Moreover, aging significantly altered the magnitude of several gene expression responses to elevated IOP, suggesting that altered gene expression dynamics within the ONH may contribute to the increased risk of glaucomatous neuropathy with aging.
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