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Wennan Lu, Ying Guo, Jonathan Huwe, Alan M. Laties, Claire H. Mitchell; Pressure, Purines And Cytokines; Early Response Genes Upregulated By Short Term IOP Elevation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5345. doi: https://doi.org/.
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Short term elevations in intraocular pressure (IOP) may effect, but not necessarily kill, retinal ganglion cells. Such short term IOP increases may trigger both protective as well as detrimental responses, and thus the identification of genes changed early on in response to rises in IOP is of interest. Previous work suggests pressure can trigger a rapid release of ATP from the retina, while other findings imply pressure can alter cytokine levels. As such, we asked whether short term IOP elevations led to rapid change in the expression of key purinergic or cytokine genes.
The Controlled Elevation of IOP (CEI) model developed by Morrison and colleagues provides a method to examine rapid changes in gene expression induced by increases in IOP. The CEI model was adapted, whereby IOP was raised to 50 mm Hg for 4 hrs (CEI 50/4) in one eye of an adult Sprague Dawley rat by cannulating the anterior chamber with sterile saline. Retinal blood flow was maintained throughout. Whole retinas were removed 1 or 5 days later, with subsequent RNA extraction and quantitative PCR.
The short term IOP elevation induced by CEI 50/4 led to upregulation in both purinergic and cytokine genes. When assesses 1 day after pressure elevation, extracellular ATP marker NTPDase1, UDP receptor P2Y6 and cytokine IL-6 were all significantly upregulated, as was transcription factor ATF3. After 5 days, levels of IL-6 had largely reduced while ATF3, P2Y6 and NTPDase1 remained elevated. Of note, CEI 50/4 did not alter levels of BAX or cyclin D1 after either 1 or 5 days, suggesting this model does not lead to substantial cell death.
The upregulation of ATP marker NTPDase1 in a rat model of short term IOP elevation suggests that pressure triggers a release of ATP in vivo as it does in vitro. Elevation at 1 and 5 days suggests the release may be both rapid and sustained. These results also confirm a role for IL-6 in the early response to short term IOP elevation, but suggest this elevation is more transient. These changes are likely to be independent of cell death.
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