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

doi:10.1172/JCI69774

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

Journal article

Open access

Peer reviewed

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 and Val C Sheffield

The Journal of clinical investigation, Vol.124(5), pp.1956-1965

05/01/2014

DOI: 10.1172/JCI69774

PMCID: PMC4001532

PMID: 24691439

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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.

Details

Title: Subtitle: Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma
Creators: Gulab S Zode - Department of Pediatrics and
Arti B Sharma - Department of Pediatrics and
Xiaolei Lin - Department of Pediatrics and
Charles C Searby - Department of Pediatrics and
Kevin Bugge - Department of Pediatrics and
Gun Hee Kim - Department of Pediatrics and
Abbot F Clark - Department of Pediatrics and
Val C Sheffield - Department of Pediatrics and
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.124(5), pp.1956-1965
DOI: 10.1172/JCI69774
PMID: 24691439
PMCID: PMC4001532
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Language: English
Date published: 05/01/2014
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
Record Identifier: 9984065383002771

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