Knock-Down of Glucocorticoid Receptor Beta (GRβ) Enhances the Ocular Hypertensive Response to Dexamethasone in C57BL/6J Mice.

Topical ocular treatment with glucocorticoids (GCs) yields an increase in intraocular pressure (IOP) in a subset (~35-40%) of the human population, known as steroid responders. If treatment is continued, this ocular hypertension (OHT) can develop into GC-induced glaucoma. In mice, the GC-mediated OHT response is modulated by the GC receptor, which exists as two major splice variants, GRα and GRβ, in the TM cell cytosol. GRα contains a GC-binding domain. Following GC binding, the GRα-GC complex enters the TM cell nucleus and transactivates genes associated with increased synthesis/export of extracellular matrix (ECM), causing OHT. GRβ has no ligand-binding domain but appears to inhibit gene transactivation by the GRα-GC complex. We previously described the effects of over-expression of GRβ on the GC-induced OHT response on IOP in mice. Here, we investigated the effect of the GC Dexamethasone (DEX) on the OHT response in C57BL/6J mice, under conditions of GRβ knockdown. A total of 20 × C57BL/6J mice (♀), aged 3-4½ months were used. Animals were weighed. Baseline (BL) conscious IOP measurements (TonoLab) and direct ophthalmoscopy (Keeler Instruments Specialist Model Ophthalmoscope) assessments were made. Animals were divided into 4 cohorts (n = 5/cohort), and anesthetized (isoflurane (2.5%) and O