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X Zhang, T Yorio; Expression of Human Glucocorticoid Receptor Alpha and Beta Isoforms in Human Trebecular Meshwork Cells and Their Regulation by Dexamethasone . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1022.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Glucocorticoids (GCs), a family of steroids, exert their effects through their interaction with glucocorticoid receptors (GR), known as ligand-dependent transcription factor. Human GR exists in two forms, GRα and GRß. GRα has been observed to bind to GCs and regulate gene expression.GRß does not bind GC and is transcriptionally inactive and might function as dominant negative inhibitor of GRα activity. GCs produce many cellular and morphologic changes in trabecular meshwork (TM) and increase aqueous outflow resistance in certain populations. Approximately 40% of the general population are ocular steroid responders. It is possible that the expression pattern of GR in TM may be subject to major regulatory variation. Currently, we investigated the expression of GR isoforms in normal and glaucomatous TM cells. Methods: Cultured transformed normal tTM5 and steroid sensitive glaucomatous tTM3 and primary normal SNTM1 and glaucomatous SGTM 152-99 cells were used. Cells were treated with control and dexamethasone (Dex 100nM) for 72 hours. Cytosol and nuclear fractions were isolated respectively and western blotting analysis was performed using non-specific GR and GRß specific antibodies. Results: Both GRα and GRß isoforms were present in these TM cells. GRα was predominant in cytoplasm. Dex treatment caused GRα translocation into the nuclear fraction in all these cells, and induced a ligand dependent down-regulation of GRα in normal tTM5, SNTM1 and glaucomatous SGTM152-99, except glaucomatous tTM3 which did not show a reduction in GRα amount. GRß was present in both the cytosol and nuclear fractions. Comparing with control, Dex treatment increased the GRß level in the nuclear fraction, but decreased it in cytoplasm fraction in both normal transformed tTM5 and primary SNTM1. However there was a decrease of GRß in nuclear fraction in glaucomatous tTM3 and no change of GRß in glaucomatous SGTM152-99 under the Dex treatment. Conclusion: Dex treatment increased the ratio of GRß/GRα in nuclear fraction in normal TM cells. The increase in nuclear GRß following Dex treatment and the concomitant reduction in GRα could account for the lack of steroid responsiveness in normal individuals.
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