Mechanistic Insights into Glucocorticoid-Induced Ocular Hypertension Using Differences in Mouse Strain Responsiveness

Abstract

Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents. Unfortunately, many people experience negative adverse 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 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. Dexamethasone treatment in these strains led to elevated intraocular pressure compared with the GC nonresponder strains DBA/2J.Gpnmb⁺, 129P3/J, and BALB/cJ. Transcriptomic analysis of responder and nonresponder mouse strains revealed novel trabecular meshwork biomarkers of GC-OHT susceptibility involving enrichment of molecular pathways unique to this response. The present study identifies putative mechanisms underlying GC-OHT and provides insight into the pathogenesis of the clinically similar but more prevalent primary open-angle glaucoma.