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bioRxiv · 10.1101/2025.07.02.662542

Mechanistic insights into glucocorticoid-induced ocular hypertension using differences in mouse strain responsiveness

Patel, P. D.·Patel, G. C.·Millar, J. C.·Feris, S.·Curry, S.·Geisert, E. E.·Clark, A. F.
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Abstract

Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents. Unfortunately, many people experience negative side-effects associated with long term GC therapy, developing GC-induced ocular hypertension (GC-OHT), which can lead to secondary glaucoma. Approximately, 40% of the treated individuals are susceptible to GC-OHT. Seventy years since this discovery, the molecular mechanisms underlying GC-OHT remain unclear. We previously developed a mouse model of GC-OHT delivering the potent GC dexamethasone (DEX) and observed strain-specific disparities in the development of GC-OHT. We now compare phenotypic and transcriptomic differences between five genetically distinct inbred mouse strains to identify biomarkers of GC susceptibility, and to better understand the molecular mechanisms of GC-OHT. Like humans, mouse strains differ in their ability to develop GC-OHT. Phenotypic characterization revealed that C57BL/6J and C3H/HeJ mice are GC responders and more susceptible to develop GC-OHT. DEX treatment in these strains led to elevated IOP compared to the GC non-responder strains DBA/2J.Gpnmb+, 129P3/J, and BALB/cJ. Transcriptomic analysis of responder and non-responder mouse strains revealed novel trabecular meshwork (TM) biomarkers of GC-OHT susceptibility involving enrichment of molecular pathways unique to this response. Our study identifies putative mechanisms underlying GC-OHT and provides insight into the pathogenesis of the clinically similar but more prevalent primary open-angle glaucoma.

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Patel, P. D., Patel, G. C., Millar, J. C., Feris, S., Curry, S., Geisert, E. E., Clark, A. F.. 2025-07-05. Mechanistic insights into glucocorticoid-induced ocular hypertension using differences in mouse strain responsiveness. https://doi.org/10.1101/2025.07.02.662542

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