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Wennan Lu, HuiLing Hu, Jean Sévigny, B'Ann T. Gabelt, Paul L. Kaufman, Elaine C. Johnson, John C. Morrison, Gulab S. Zode, Val C. Sheffield, Xiulan Zhang, Alan M. Laties, Claire H. Mitchell; Rat, Mouse, and Primate Models of Chronic Glaucoma Show Sustained Elevation of Extracellular ATP and Altered Purinergic Signaling in the Posterior Eye. Invest. Ophthalmol. Vis. Sci. 2015;56(5):3075-3083. doi: 10.1167/iovs.14-15891.
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The cellular mechanisms linking elevated IOP with glaucomatous damage remain unresolved. Mechanical strains and short-term increases in IOP can trigger ATP release from retinal neurons and astrocytes, but the response to chronic IOP elevation is unknown. As excess extracellular ATP can increase inflammation and damage neurons, we asked if sustained IOP elevation was associated with a sustained increase in extracellular ATP in the posterior eye.
No ideal animal model of chronic glaucoma exists, so three different models were used. Tg-MyocY437H mice were examined at 40 weeks, while IOP was elevated in rats following injection of hypertonic saline into episcleral veins and in cynomolgus monkeys by laser photocoagulation of the trabecular meshwork. The ATP levels were measured using the luciferin-luciferase assay while levels of NTPDase1 were assessed using qPCR, immunoblots, and immunohistochemistry.
The ATP levels were elevated in the vitreal humor of rats, mice, and primates after a sustained period of IOP elevation. The ecto-ATPase NTPDase1 was elevated in optic nerve head astrocytes exposed to extracellular ATP for an extended period. NTPDase1 was also elevated in the retinal tissue of rats, mice, and primates, and in the optic nerve of rats, with chronic elevation in IOP.
A sustained elevation in extracellular ATP, and upregulation of NTPDase1, occurs in the posterior eye of rat, mouse, and primate models of chronic glaucoma. This suggests the elevation in extracellular ATP may be sustained in chronic glaucoma, and implies a role for altered purinergic signaling in the disease.
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