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T. Yorio, A.F. Clark, X. Zhang; Expression of Glucocorticoid Receptor Beta and Its Regulation in Glucocorticoid Responsiveness in Glaucoma . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4387.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:The ocular administration of a glucocorticoid (GC) results in an increase in intraocular pressure in approximately 35% of the general population and in 90% of Primary Open Angle Glaucoma (POAG) patients. Why these patients respond to this high rate is not clear. It has been shown that GCs, like dexamethasone (Dex), increase aqueous humor outflow resistance associated with cellular changes in the trabecular meshwork (TM) cells, including enhancing the expression of the protein myocilin, a known glaucoma gene. These GC–induced changes are mediated through the glucocorticoid receptor alpha (GRα). However, glucocorticoid receptor beta (GRß) is associated with GC resistance in many diseases, including asthma. Currently we are investigating the potential role of GRß in regulating GC sensitivity in glaucoma. Methods:5 Normal and 6 glaucomatous TM cell lines were used.Western blot for cytosolic and nuclear fractions were performed to investigate the expression of GRß in TM cells and its regulation by Dex. The expression and regulation of GRα by Dex were confirmed in these TM cells. Immunocytochemistry was used to compare the subcellular expression of GRß between multiple normal and glaucomatous TM cell lines. Furthermore, Transfection and overexpression of GRß was conducted in normal and glaucomatous TM cell lines and both Western Blot and Confocal Microscopy were used to detect the regulation of GRß in the Dex–induced myocilin expression in these TM cell lines. Results: Western blot detected that GRß was expressed in all these trabecular meshwork cell lines. GRß was expressed not only in the nucleus but also in the cytoplasm. Interestingly, most normal TM cell lines have relatively high amount of GRß expression, especially in the nucleus compared to glaucomatous TM cell lines. Dex treatment did not change the expression of GRß, while caused the translocation of GRα from the cytoplasm to the nucleus and also a time–dependent down–regulation of GRα. Strikingly, overexpression of GRß attenuated the Dex–inducted expression of myocilin in these GRß transfected TM cell lines. Conclusions: We have, for the first time, detected the expression of GRß in TM cells. The low expression of GRß in glaucomatous TM cells was highly correlated with the high sensitivity to GCs in POAG subjects. The up–regulation of the GRß expression in TM cells can suppress glucocorticoid cellular responses. These results support the contention that GRß acts as a negative regulator of the GC–GRα response and the lower amount of GRß in the nucleus of glaucomatous TM cells could explain the increased GC response seen in glaucoma patients.
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