Glucocorticoid receptor GRβ regulates glucocorticoid-induced ocular hypertension and glaucoma in mice




Liu, Yang
Patel, Gaurang
Millar, J. Cameron
Clark, Abbot


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Purpose: Glucocorticoid (GC) induced ocular hypertension (OHT) is a serious side effect of prolonged GC therapy and if left untreated it can lead to iatrogenic glaucoma and permanent vision loss. The Alternatively spliced isoform of glucocorticoid receptor GRβ acts as a dominant negative regulator of GC activity. Our previous studies have shown that GRβ regulates GC responsiveness and that overexpressing GRβ in trabecular meshwork (TM) cells inhibits GC-induced and glaucomatous damage in TM cells. The purpose of this study was to determine whether increased expression of GRβ can reverse GC-induced OHT in mice. Methods: Mouse trabecular meshwork cells (MTM) were transduced with Ad5.null or Ad5.hGRβ expression vectors at MOI-50. After 24 hours MTM cells were treated with dexamethasone (DEX) or vehicle control (0.1% ethanol). To generate GC-OHT, C57BL/6J mice received weekly bilateral periocular (administrated through conjunctival fornix) injections of dexamethasone acetate (DEX-Ac, 200ug/eye). Several weeks after DEX-Ac administration, mouse eyes were injected intravitreally with Ad5.null or Ad5.hGRβ expression vectors (3x107 pfu/eye) to transduce the TM. Nighttime intraocular pressure (IOP) was measured using a TonoLab rebound tonometer, and outflow facilities were measured in living mice using our constant flow infusion technique. Fibronectin and collagen I expression were evaluated using immunoblotting of mouse anterior segment tissues. The unpaired Student’s t-test (2-tailed) and One-way ANOVA were used for statistical analysis. Results: DEX treatment of MTM cells increased fibronection expression, whereas transduction of MTM cells with Ad5.hGRβ maintained fibronectin expression at control levels as shown by immunocytochemistry. DEX-Ac significantly increased IOP from days 3-44 (n=23, p Conclusion: Overexpression of GRβ in the TM of mouse eyes reversed GC-OHT. GRβ gene therapy may be a useful therapeutic approach to treat GC-OHT and glaucoma.


Research Appreciation Day Award Winner - 2017 North Texas Eye Research Institute - 1st Place Graduate Student