Glucocorticoid receptor GR? regulates glucocorticoid-induced ocular hypertension in mice.

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 GR? acts as dominant negative regulator of GR activity, and it has been shown that overexpressing GR? 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 GR? isoform in the TM of mouse eyes treated with GCs, to precisely dissect the role of GR? in regulating steroid responsiveness. We show that overexpression of GR? inhibits GC effects on MTM cells in vitro and GC-induced OHT in mouse eyes in vivo. Ad5 mediated GR? overexpression reduced the GC induction of fibronectin, collagen 1, and myocilin in TM of mouse eyes both in vitro and in vivo. GR? also reversed DEX-Ac induced IOP elevation, which correlated with increased conventional aqueous humor outflow facility. Thus, GR? 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 GR? in regulating GC-OHT and GC-mediated gene expression in the TM.

SUBMITTER: Patel GC 

PROVIDER: S-EPMC5770444 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature