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Gaurang C Patel, Yang Liu, J Cameron Millar, Abbot F Clark; Glucocorticoid receptor GRβ regulates glucocorticoid-induced ocular hypertension and glaucoma in mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):849.
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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 reversed GC- induced OHT in mice.
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 TM. Intraocular pressure (IOP) was measured using 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 from mouse anterior segment tissues. Unpaired Student’s t-test (2-tailed) and One-way ANOVA were used for statistical analysis.
DEX-Ac significantly increased IOP from days 3-44 (n=23, p<0.0001), with a maximum IOP increase of 10 mmHg compared to vehicle control eyes. GRβ transduction of TM at day 19 after DEX-Ac induced OHT significantly lowered IOP (n=14, p<0.001) within 7 days to basline IOPs, thus reversing GC-OHT in mouse eyes. DEX-Ac significantly decreased the outflow facility (n=10, p<0.01) and GRβ transduction returned the outflow facility to normal levels (n=9, p<0.05). Increased expression of fibronectin and collagen I was observed in DEX-Ac treated mice compared to controls and GRβ transduced mouse eyes.
Overexpression of GRβ in the TM of mouse eyes reversed GC-OHT. GRβ gene therapy may be a useful therapeutic approach to treat glucocorticoid-induced ocular hypertension and glaucoma.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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