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W.O. Cepurna, L. Jia, E.C. Johnson, J.C. Morrison; Aging Increases Susceptibility to Intraocular Pressure (IOP) and Alters Retinal Gene Expression Responses in the Rat . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1243.
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© ARVO (1962-2015); The Authors (2016-present)
Aged animals may be used to model the risk factor of aging in glaucoma pathogenesis. In this study, we exposed adult and aged eyes to elevated IOP and compared resulting optic nerve injury and retinal gene expression responses.
Chronic unilateral IOP elevation was produced in Adult (8 month) and Aged (28 month) Brown Norway rats by episcleral vein saline injection (N=134) and IOP was measured frequently. Retinas were collected and frozen at two time points, 10 days (short term) and at 5 weeks post–injection. Optic nerve cross sections were graded for degree of degeneration. Retinal RNA levels were quantified by real time RT–PCR and analyzed by 2–way ANOVA based on treatment group and cumulative IOP history.
Aging and cumulative IOP history significantly increased optic nerve injury following both short term (p<0.05) and 5 week (p<0.01) elevated IOP exposure. In the retina, age did not affect some gene expression responses to elevated IOP, including those for neurotrophin receptors. In both age groups, elevated IOP resulted in increased p75 NTR mRNA levels at both experimental durations and moderately reduced TrkB mRNA levels after 5 weeks. In contrast, while tissue inhibitor of metalloproteinases–1 (Timp1) mRNA levels were dramatically upregulated to 23±8 and 45±9 fold in short term and 5 week adult groups, respectively, increases were 3 to 4–fold less dramatic in the related aged groups (p<0.01). Message levels for two proteins localized to retinal ganglion cells (RGC), neurofilament H and thy1, were significantly reduced by both aging and cumulative IOP exposure at both durations (p<0.0001). Aging resulted in decreased RGC GAP43 mRNA levels, but elevated IOP produced parallel increases in the message at both exposure durations. Retinal JunB mRNA levels were significantly increased in both age groups in response to elevated IOP. However, further increases due to aging were statistically significant only at 5 weeks. cJun responses were similar, but less in magnitude.
By modeling glaucoma in the aged rat eye, we demonstrate an increased susceptibility of the aged optic nerve to elevated IOP that is correlated with specific alterations in retinal gene expression. These may suggest molecular mechanisms for the increased risk of glaucoma associated with human aging. Additionally, we illustrate the importance of considering age in modeling glaucoma in laboratory animals.
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