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C. E. Crosson, P. W. Yates, J. A. Fant; Prolonged Dexamethasone Exposure Reduces Adenosine A1 Agonist Signaling in the Trabecular Meshwork Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):156.
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The chronic administration of steroids can increase IOP; however, the cellular mechanisms responsible for this rise in IOP are not understood. Previous studies have provided evidence that the activation of adenosine A1 receptors in the trabecular meshwork by endogenous purines can regulate outflow facility and IOP. The current studies investigate if dexamethasone exposure of these cells alters purinergic signaling.
Cultured primary human trabecular meshwork (HTM) cells were incubated in the presence or absence of dexamethasone (10-6 mol/L) for 14 days. The activation (i.e., phosphorylation) of ERK 1/2 pathway was induced by the addition of the adenosine A1 agonist, CHA (10-7 mol/L). The activation of ERK 1/2 and the expressions of dual-specificity phosphatase, MKP-1 and the adenosine receptor were determined by Western blot analysis and/or quantitative RT-PCR.
In primary HTM culture, the addition of CHA produced a rapid increase in ERK 1/2 activation that peaked within 10 minutes. This increase in ERK 1/2 activation remained elevated for 30 minutes and then slowly returned to basal levels between 60 and 120 minutes post-administration. Exposure of trabecular cells to DEX for 14 days did not produce any significant change in peak ERK activation; however, dexamethasone treatment significantly accelerated the deactivation (i.e., dephosphorylation) of ERK 1/2 by over 70%. In cells treated with dexamethasone, no change in the expression of ERK 1/2 or adenosine A1 receptor levels was measured. However, dexamethasone treatment significantly increase the expression of dual-specificity phosphatase, MKP-1, by more than 8-fold. In cells treated with dexamethasone, the addition of doxorubicin, a known repressor of MKP expression, for 4 hours prior to CHA administration reversed the effects of dexamethasone treatment.
These studies demonstrate that dexamethasone treatment can suppress adenosine-A1 agonist activation of ERK 1/2 in HTM cells. The suppression appears to be due to the upregulation of MKP-1 increasing the rate of ERK 1/2 inactivation. Thus, reduced ERK 1/2 activation in the trabecular meshwork may play a role in steroid-induced glaucoma.
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