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Varun Kumar, Ali Shariati, Kathy Heng, Angela Oh, Louise Alessandra Mesentier Louro, Yaping Joyce Liao; Assessment of Endoplasmic Reticulum Stress Response after Diabetic Ischemic Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3559.
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Non-arteritic anterior ischemic optic neuropathy (NAION) is due to loss of oxygen to the anterior optic nerve, a watershed area and leads to degeneration of retinal ganglion cell (RGC) body and axons as well as loss of optic nerve oligodendrocytes and demyelination. NAION in animals with diabetes mellitus (DM) leads to significant increase in retinal edema, VEGF levels, and greater loss of RGCs. Diabetes is also associated with increased risk of metabolic stress, which is particularly prominent in cells with high metabolic activity such as RGCs and oligodendrocytes and may contribute to the development of NAION and bilateral involvement. In this study, we investigated endoplasmic reticulum (ER) stress responses after experimental NAION.
We induced NAION and streptozotocin-induced diabetic NAION in over 80 adult C57BL/6 mice using photochemical thrombosis and performed morphometric analyses of horizontal frozen sections or whole mount preparations of the retinae and optic nerves. Immunohistochemistry was performed using antibodies against CHOP (marker of proapoptotic ER pathway activation), olig2 (marker of oligodendrocytes), Brn3A (marker of RGCs), and others.
After 3 weeks of diabetes, there was little expression of C/EBP homologous protein (CHOP) in the retina or optic nerve; after 2 months, there was near confluent expression of CHOP in optic nerve oligodendrocytes but not in Brn3A+ RGCs. One day after NAION, there was significant increase in expression of CHOP in Brn3A+ RGCs and in optic nerve olig2+ oligodendrocytes (p<0.001). Animals with diabetic NAION developed significantly greater CHOP upregulation compared with those with NAION (p=0.02) or diabetes (p=0.02). Treatment with insulin significantly reduced CHOP expression (p=0.001).
In diabetic NAION, significant activation of the proapoptotic PERK-eILF2α-CHOP pathway occurred by day 1 in retinal ganglion cells and in optic nerve oligodendrocytes. This ER stress was significantly reduced by treatment with insulin, indicating reversible metabolic derangement with glycemic control alone.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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