Abstract
Prolonged glucocorticoid (GC) therapy can cause GC-induced ocular hypertension (OHT), which if left untreated progresses to iatrogenic glaucoma and permanent vision loss. The alternatively spliced isoform of glucocorticoid receptor GRβ acts as dominant negative regulator of GR activity, and it has been shown that overexpressing GRβ in trabecular meshwork (TM) cells inhibits GC-induced glaucomatous damage in TM cells. The purpose of this study was to use viral vectors to selectively overexpress the GRβ isoform in the TM of mouse eyes treated with GCs, to precisely dissect the role of GRβ in regulating steroid responsiveness. We show that overexpression of GRβ inhibits GC effects on MTM cells in vitro and GC-induced OHT in mouse eyes in vivo. Ad5 mediated GRβ overexpression reduced the GC induction of fibronectin, collagen 1, and myocilin in TM of mouse eyes both in vitro and in vivo. GRβ also reversed DEX-Ac induced IOP elevation, which correlated with increased conventional aqueous humor outflow facility. Thus, GRβ overexpression reduces effects caused by GCs and makes cells more resistant to GC treatment. In conclusion, our current work provides the first evidence of the in vivo physiological role of GRβ in regulating GC-OHT and GC-mediated gene expression in the TM.
Highlights
Since their discovery in 1950’s, glucocorticoids (GCs) are the most widely prescribed medications worldwide because of their broad spectrum of anti-inflammatory and immunomodulatory activities[1,2]
The beads were phagocytized by mouse trabecular meshwork (MTM) cells and MTM cells with engulfed magnetic beads were separated from non-trabecular meshwork (TM) cells by applying a magnetic field
If left untreated, GC-ocular hypertension (OHT) progresses to secondary open angle glaucoma, causing glaucomatous optic neuropathy and permanent vision loss
Summary
Since their discovery in 1950’s, glucocorticoids (GCs) are the most widely prescribed medications worldwide because of their broad spectrum of anti-inflammatory and immunomodulatory activities[1,2]. GCs alter TM cellular structure and functions, including increasing TM cell and nucleus size[17], reorganizing the cytoskeleton (forming cross-linked actin networks (CLANs))[23,24,25,26,27], inhibiting phagocytosis[28], inhibiting cell proliferation and migration, altering cellular junctional complexes[29], and increasing extracellular matrix deposition[30,31,32,33,34] These biochemical and morphological changes in the TM affect TM stiffness and impair TM functions, causing increased aqueous humor outflow resistance and elevated IOP, clinically similar to what is observed in POAG patients. We used an adenoviral expression vector serotype (Ad5) that selectively transduces the TM51–55 to overexpress the hGRβ isoform using our newly developed mouse model of DEX- induced OHT56 This reproducible model is easy to run and captures many aspects of GC-induced OHT observed in humans including elevated IOP, reduction in the aqueous humor outflow facility, biochemical changes in TM, and reversibility of ocular hypertension after discontinuing GC treatment[56]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
