Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma
Gulab S. Zode, … , Abbot F. Clark, Val C. Sheffield
Gulab S. Zode, … , Abbot F. Clark, Val C. Sheffield
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(5):1956-1965. https://doi.org/10.1172/JCI69774.
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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 1

Topical ocular dexamethasone induces glaucoma in mice.

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Topical ocular dexamethasone induces glaucoma in mice. (A) Elevated IOP ...
(A) Elevated IOP in dexamethasone-treated C57BL/6 mice. Topical ocular vehicle (sterile PBS) or dexamethasone (0.1%) was administered 3 times daily for up to 20 weeks. IOP measurements of dexamethasone-treated (n = 20–24) and vehicle-treated (n = 20) mice are shown from week 0 to 6 of treatment. **P < 0.005, ***P < 0.0001, unpaired t test. (B) Progressive RGC functional loss in dexamethasone-treated mice. PERG amplitudes (P50-N95) in vehicle and dexamethasone-treated mice at 5 (n = 5), 15 (n = 10), and 20 (n = 6) weeks of treatment. (C and D) Loss of RGCs in dexamethasone-treated mice. (C) Representative images of Nissl-stained whole-mount retinas from mice treated for 20 weeks with vehicle or dexamethasone. (D) Remaining cells in ganglion layer were counted in the periphery of the retina. n = 5 (vehicle); 10 (dexamethasone). **P = 0.0045, unpaired t test. (E and F) Progressive optic nerve degeneration in mice treated with dexamethasone for 10 or 15 weeks. Optic nerve sections were stained with PPD (E), and mean axon counts (F) were compared in dexamethasone- (n = 8) and vehicle-treated (n = 7–10) mice. *P = 0.0174, **P = 0.0013 vs. vehicle, unpaired t test. Scale bar: 10 μm.