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Abbot F. Clark, J Cameron Millar, Gaurang Patel; Glucocorticoid-Induced Ocular Hypertension in Mice Requires Glucocorticoid Receptor Transactivation Activity. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6037. doi: https://doi.org/.
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Glucocorticoid (GC)-induced ocular hypertension (OHT) is a serious side-effect of prolonged GC therapy that can lead to iatrogenic glaucoma and permanent vision loss. GCs act through the glucocorticoid receptor (GR), and this ligand activated receptor can regulate transcription both through transactivation (TA) and transrepression (TR) mechanisms. However, there is no evidence showing which of these two transcription mechanisms play a role in the multitude of GC effects on the TM and on the development of GC-OHT.
We have used GRdim homozygous mice (on a C57BL/6 background) and C57BL/6J WT mice as controls. In GRdim mice, the GR has been mutated to prevent receptor dimerization and binding to promoter GREs. Therefore, GRdim mice retain GC TR but lack TA activities. Primary mouse TM cells were isolated from WT and GRdim mice. DEX-induced expression of fibronectin (FN), myocilin (MYOC), collagen I (Col I), and cross-linked actin networks (CLANs) was evaluated in WT and GRdim MTM cells (n=3 independent MTM strains). DEX-OHT was generated by weekly binocular periocular DEX-Ac injections, and nighttime IOPs were measured using a TonoLab rebound tonometer. Outflow facilities were measured using our constant flow infusion technique. DEX-induced expression of several proteins in the TM of mouse eyes was evaluated by immunofluorescent staining.
DEX treated WT MTM cells significantly increased the expression of FN and MYOC (p<0.05) as well as CLAN formation (p<0.0001). However, these DEX responses did not occur in cultured GRdim MTM cells. Weekly DEX-Ac administration significantly elevated IOP in WT mice from 4-39 days (n=12-15; p<0.0001) and significantly decreased the outflow facility by more than 50% (n=5-8; p<0.001). In contrast, weekly DEX-Ac treatment did not elevate IOP (n=8-12) or change the aqueous outflow facility (n=7-8) of GRdim mice. There was increased expression of FN, Col I, and a-SMA in the TM tissues of DEX-OHT WT mice, but very little change in the expression of the DEX-induced proteins in GRdim mice.
GCs have numerous effects of the TM, although which are responsible for GC-OHT are still unknown. We have shown for the first time that GC transactivation is responsible for GC-OHT in mice. This discovery will aid in the discovery and development of novel compounds that retain GC anti-inflammatory activities but are devoid of generating GC-OHT.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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