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R.T. Libby, L.A. Wilson, I.M. Cosma, A. Snow, R.S. Smith, S.W. M. John; Genetically Reducing Blood Pressure Increases Susceptibility to Glaucomatous Neurodegneration in DBA/2J Mice . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1296.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose.Low blood pressure has been hypothesized to exacerbate glaucomatous neurodegeneration. To test this hypothesis, we genetically decreased blood pressure in the DBA/2J mouse glaucoma model. Methods: A null allele of angiotensin receptor 1 (Agtr1), a gene known to be critical in blood pressure regulation, was backcrossed into DBA/2J mice. DBA/2J Agtr1+/+ and Agtr1–/– mice were analyzed. Blood pressure was measured using a tail cuff method. All mice were clinically assessed and IOP was measured at multiple ages to ensure that Agtr1 deficiency did not change the glaucomatous IOP insult. Neurodegeneration was evaluated by scoring the optic nerves for degeneration. Optic nerves were scored as being either mild, moderate, or severe based on the amount of axonal loss. This scoring system is highly repeatable, and has been validated with axon counts. Retinal histology was analyzed using standard histological techniques. Results: Similar to published reports, complete AGTR1 deficiency (Agtr1–/–) decreased the systolic blood pressure of DBA/2J mice by approximately 25 mmHg. Agtr1 genotype did not change IOP at any of the ages examined (3, 10.5 and 11 months; all P values > 0.2). As a population, Agtr1–/– mutant mice had significantly more optic nerve damage compared to Agtr1+/+ mice at 10.5 months of age (% mild, moderate, severe; Agtr1+/+ 53, 9, 38; Agtr1–/– 16, 9, 75; P<0.001; n >30 for each genotype). At 11.5 months, the population of Agtr1–/– mice continued to be more severely affected (P = 0.03, n > 30 for each genotype). Preliminary studies also suggest that low blood pressure can alter the susceptibility of different retinal cell types to IOP–induced damage. In Agtr1–/– mice, elevated IOP and decreased blood pressure seems to result in focal photoreceptor and inner nuclear layer neuronal loss, which is rarely present in DBA/2J mice in our colony. Conclusions: Agtr1 deficiency decreased blood pressure in DBA/2J mice. In an environmentally and genetically controlled experiment, we were able to use Agtr1 deficiency to test whether altered blood pressure contributed to the rate and/or amount of glaucomatous neurodegeneration. Decreased blood pressure increased the likelihood of glaucomatous neurodegeneration in DBA/2J mice. These data support the hypothesis that blood pressure is an important factor in determining susceptibility to glaucomatous neurodegeneration.
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