Phenotypic and transcriptomic comparison of genetically distinct mouse strains for susceptibility to glucocorticoid-induced ocular hypertension (GC-OHT)

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) leading 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 all humans develop GC-OHT when treated with GCs. The ones that develop GC-OHT are called ‘responders’ whereas the ones that do not respond to GCs are called ‘non-responders’. 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 gene expression using transcriptomic analysis.

Methods: After measurement of baseline IOP, various mouse strains (B6, D2.gpnmb⁺, BALB/cJ, 129P3/J, C3H/HeJ) were treated with weekly periocular injections of potent GC 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 isoflurane anesthetized mice. “TM ring” tissue and underlying sclera was carefully collected, and mRNA libraries were prepared for sequencing. Differential expression analysis was performed to identify DEX-induced changes within each strain. Furthermore, Ingenuity Pathway Analysis (IPA) was used to identify DEX-altered pathways in each strain and compare differences between responder and non-responder strains.

Results: B6 and C3H/HeJ mice robustly and reproducibly develop DEX-OHT with ΔIOP of 5-8 mmHg (P<0.0001). In contrast, D2.gpnmb⁺, 129P3/J, and BALB/cJ mice were resistant to the development of DEX-OHT. Differential analysis of gene expression between mouse strains showed novel DEX-responsive genes in all strains. Moreover, comparison of mouse strains using IPA showed similarities in the pathway and networks of the responder strains (B6 and C3H/HeJ).

Conclusions: As observed in humans, we find that there are differences in GC responsiveness and the ability to develop GC-OHT among mouse strains. Transcriptomics evidence suggests that responder strains share common pathways that contribute towards development of GC-OHT. These studies will reveal the molecular mechanisms responsible for GC-OHT as well as provide insights into the pathogenesis of POAG.