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Gulab S Zode, Charles Searby, Kevin Bugge, Abbot F Clark, Val Sheffield; The role of ER stress in the trabecular meshwork of human glaucoma and mouse models of glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5651.
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To examine whether increased ER stress in the trabecular meshwork (TM) is associated with elevation of intraocular pressure (IOP) and to determine whether reducing ER stress in the TM rescues glaucoma in mouse models of glaucoma. Furthermore, we will determine whether ER stress is increased in human glaucomatous TM.
We recently developed a mouse model of glucocorticoid-induced glaucoma and a transgenic mouse model that expresses human mutant myocilin and develops adult onset primary open angle glaucoma (Tg-MYOCY437H mice). TM tissues obtained from these mouse models were utilized to examine ER stress markers by Western blot, immumostaining and RT-PCR analysis. We utilized RT-PCR to examine XBP-1 splicing as a marker of ER stress in glaucomatous TM cells.
We demonstrate that ocular hypertension induced by topical ocular 0.1% dexamethasone (DEX) or by mutant human myocilin is associated with chronic ER stress in the TM. Both dexamethasone and mutant myocilin activate the unfolded protein response including phosphorylation of IRE-1α and elF-2α, increase levels of GRP78, GRP94, and ATF-4, and also induce pro-apoptotic transcriptional factor Chop in the TM (n=4 in each group; t-test, P<0.001). Deletion of Chop in mice reduces ER stress in the TM and prevents DEX-induced ocular hypertension (16mmHg in vehicle-treated WT mice vs 23mmHg in DEX-treated WT mice; p<0.0001, 18mmHg in DEX-treated Chop ko mice; p<0.0001, n=10 in each groups). Furthermore, the chemical chaperone sodium 4-phenylbutyrate (PBA) prevents DEX-induced ocular hypertension (19mmHg in PBA-treated mice vs 23mmHg in non PBA-treated mice, n=10) and prevents glaucoma in Tg-MYOCY437H mice by reducing ER stress in the TM. In addition, primary cultures of TM cells obtained from glaucomatous donors demonstrate a spliced form of XBP-1 compared to normal human TM cells, indicating induction of ER stress in the glaucomatous TM.
ER stress plays a critical role in ocular hypertension in glaucoma, and the reduction of ER stress via PBA can be used as a therapeutic strategy for the treatment of glaucoma.
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