Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma
Gulab S. Zode, Arti B. Sharma, Xiaolei Lin, Charles C. Searby, Kevin Bugge, Gun Hee Kim, Abbot F. Clark, Val C. Sheffield
Gulab S. Zode, Arti B. Sharma, Xiaolei Lin, Charles C. Searby, Kevin Bugge, Gun Hee Kim, Abbot F. Clark, Val C. Sheffield
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Research Article Ophthalmology

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

Abstract

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.

Authors

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

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Figure 7

Decreasing ER stress by administration of the chemical chaperone PBA reduces IOP elevation by dexamethasone.

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Decreasing ER stress by administration of the chemical chaperone PBA red...
(A–C) WT mice were given topical ocular vehicle or dexamethasone for 3 weeks. Dexamethasone-treated mice were divided into 2 groups: one received water, the other received 20 mM PBA in drinking water. (A) PBA treatment significantly protected from dexamethasone-induced IOP elevation (n = 20 per group). **P < 0.05, ***P < 0.005, 1-way ANOVA. (B and C) Western blot (B) and densitometric analysis (C) of ER stress markers in anterior segment tissues revealed that combined dexamethasone and PBA treatment reduced ER stress markers compared with dexamethasone treatment alone (n = 5 per group). (D) PBA reduced ER stress associated with dexamethasone in human TM cells. Human TM cells were treated with dexamethasone with or without 5 mM PBA. Total cell lysates were subjected to Western blot analysis for GRP78, GRP94, phosphorylated and total eIF2α, MYOC, and GAPDH.