Document Detail


Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma.
MedLine Citation:
PMID:  24691439     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2014-04-01
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  124     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2014 May 
Date Detail:
Created Date:  2014-06-06     Completed Date:  2014-06-16     Revised Date:  2014-11-14    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1956-65     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology
Dexamethasone / adverse effects*,  pharmacology
Disease Models, Animal
Endoplasmic Reticulum Stress / drug effects*,  genetics
Gene Deletion
Glaucoma, Open-Angle / chemically induced,  genetics,  metabolism*,  pathology,  prevention & control
Glucocorticoids / adverse effects*,  pharmacology
Humans
Mice
Mice, Transgenic
Phenylbutyrates / pharmacology
Trabecular Meshwork / metabolism*,  pathology
Transcription Factor CHOP / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
2R01EY016242/EY/NEI NIH HHS; K99 EY022077/EY/NEI NIH HHS; R00 EY022077/EY/NEI NIH HHS; R01 EY011298/EY/NEI NIH HHS; R01 EY10564/EY/NEI NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Ddit3 protein, mouse; 0/Glucocorticoids; 0/Phenylbutyrates; 147336-12-7/Transcription Factor CHOP; 7S5I7G3JQL/Dexamethasone; 7WY7YBI87E/4-phenylbutyric acid
Comments/Corrections

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