Journal Article

Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma

Kim, Gun Hee, Lin, Xiaolei, Sharma, Arti B., Zode, Gulab S., Bugge, Kevin, Searby, Charles C., Clark, Abbot F., Sheffield, Val C.

2014

Overview

Administration of glucocorticoids induces ocular hypertension in some patients. If untreated, these patients can develop a secondary glaucoma that resembles primary open-angle glaucoma (POAG). The underlying pathology of glucocorticoid-induced glaucoma is not fully understood, due in part to lack of an appropriate animal model. Here, we developed a murine model of glucocorticoid-induced glaucoma that exhibits glaucoma features that are observed in patients. Treatment of WT mice with topical ocular 0.1% dexamethasone led to elevation of intraocular pressure (IOP), functional and structural loss of retinal ganglion cells, and axonal degeneration, resembling glucocorticoid-induced glaucoma in human patients. Furthermore, dexamethasone-induced ocular hypertension was associated with chronic ER stress of the trabecular meshwork (TM). Similar to patients, withdrawal of dexamethasone treatment reduced elevated IOP and ER stress in this animal model. Dexamethasone induced the transcriptional factor CHOP, a marker for chronic ER stress, in the anterior segment tissues, and Chop deletion reduced ER stress in these tissues and prevented dexamethasone-induced ocular hypertension. Furthermore, reduction of ER stress in the TM with sodium 4-phenylbutyrate prevented dexamethasone-induced ocular hypertension in WT mice. Our data indicate that ER stress contributes to glucocorticoid-induced ocular hypertension and suggest that reducing ER stress has potential as a therapeutic strategy for treating glucocorticoid-induced glaucoma.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Antineoplastic Agents - pharmacology / Apoptosis / Biomedical research / Care and treatment / Control / Dexamethasone - adverse effects / Dexamethasone - pharmacology / Disease Models, Animal / Drinking water / Endoplasmic reticulum / Endoplasmic Reticulum Stress - drug effects / Endoplasmic Reticulum Stress - genetics / Gene Deletion / Glaucoma / Glaucoma, Open-Angle - chemically induced / Glaucoma, Open-Angle - genetics / Glaucoma, Open-Angle - metabolism / Glaucoma, Open-Angle - pathology / Glaucoma, Open-Angle - prevention & control / Glucocorticoids - adverse effects / Glucocorticoids - pharmacology / Humans / Hypertension / Intraocular pressure / Mice / Mice, Transgenic / Phenylbutyrates - pharmacology / Physiological aspects / Protein folding / Rodents / Trabecular Meshwork - metabolism / Trabecular Meshwork - pathology / Transcription Factor CHOP - genetics / Transcription Factor CHOP - metabolism