Abstract
Purpose :
Anti-inflammatory and immunosuppressive glucocorticoids (GCs) are widely prescribed for a variety of conditions and diseases. Unfortunately, a significant number of people experience negative side-effects associated with long term GC therapy and develop GC-induced ocular hypertension (GC-OHT) that leads to secondary glaucoma. GC-OHT shares clinical and molecular signatures with primary open angle glaucoma (POAG) making this an appropriate model to study POAG. However, not everyone develops GC-OHT when treated with GCs. The alternatively spliced isoform of the glucocorticoid receptor GRβ is expressed in the trabecular meshwork (TM) and can mitigate GC effects in the TM, including the development of GC-OHT in mice. The purpose of our study is to: (1) determine whether there are mouse strain differences in the development of GC-OHT, (2) whether resistance to develop GC-OHT is correlated with endogenous TM tissue GRβ expression, and (3) map the gene(s) responsible for GC-OHT in mice.
Methods :
After measurement of baseline IOP, various mouse strains (B6, D2.gpmnb+, BALB/cJ, 129P3/J, C3H/HeJ, BXD RI) were treated with weekly periocular injections of dexamethasone (DEX; n=5-10) or vehicle (n=5-10) in both eyes for 4-5 weeks. IOPs were measured weekly using a TonoLab rebound tonometer in conscious or isoflurane anesthetized mice. “TM ring” tissue and underlying sclera was carefully collected to measure expression of GRα and GRβ using qRT-PCR.
Results :
The mouse strains differ in their baseline IOP levels. B6 and C3H/HeJ mice robustly and reproducibly develop DEX-OHT with ΔIOP of 5-8 mmHg (P<0.0001). In contrast, D2.gpmnb+, 129P3/J, and BALB/cJ mice were resistant to the development of DEX-OHT. Preliminary data show a correlation between reduced DEX response and increased TM GRβ expression in non-responder strains. Since B6 mice are responders and D2 mice are non-responders, we are using the recombinant inbred (RI) BXD mouse strains (n>100) to map the gene(s) responsible for DEX-OHT in mice.
Conclusions :
As observed in humans, we find that there are differences in GC responsiveness and the ability to develop GC-OHT among mouse strains. Non-responsiveness appears to correlate with higher expression of GRβ in the TM, although evaluation of more mouse strains and selective knockdown of endogenous GRβ in the TM of non-responder strains will be required to confirm whether GRβ truly is responsible.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.