Endoplasmic Reticulum Stress in Retinal Vascular Degeneration: Protective Role of Resveratrol

PURPOSE. Endoplasmic reticulum (ER) stress has been demonstrated to contribute to neurodegeneration in multiple ocular diseases. However, whether ER stress can induce vascular degeneration in the retina remains unknown. We investigated the possible role of ER stress in retinal vascular degeneration in vivo, and the effects of resveratrol on tunicamycin and ischemia and reperfusion (I/R)-induced retinal vascular degeneration. METHODS. Different dosages of tunicamycin, an ER stress inducer, were injected into the vitreous of mouse eyes. Retinal I/R injury was induced by elevating the intraocular pressure for 60 minutes followed by reperfusion in mice. Two dosages of resveratrol (5 and 25 mg/kg body weight per day) were administrated 2 days before retinal I/R injury, while 100 mu M resveratrol were injected into the vitreous together with tunicamycin. Formation of acellular capillaries was assessed 7 days after I/R injury and tunicamycin injection, while cell bodies in ganglion cell layer and brain-specific homeobox/POU domain protein 3A (Brn3a) staining on retinal flat-mounts were analyzed 4 days after I/R injury. ER stress markers, including eukaryotic initiation factor 2 alpha (eIF2 alpha), CCAAT enhancer-binding protein homologous protein (CHOP), immunoglobulin binding protein (Bip), inositol requiring enzyme 1 alpha (IRE1 alpha), C-jun N-terminal kinase (JNK)1/2 and Xbp1 splicing, were examined by RT-PCR, or Western blots or immunostaining from retinas 1 or 2 days after tunicamycin injection and I/R injury. RESULTS. Tunicamycin caused ER stress and capillary degeneration in vivo, both of which were inhibited by resveratrol. Pretreatment of high dosage of resveratrol also significantly inhibited retinal I/R injury-induced capillary degeneration; however, neither of the dosages prevented the injury-induced neurodegeneration. Levels of CHOP, phosphorylated eIF2 alpha, IRE1 alpha, phosphorylated JNK1/2, Xbp1 splicing and Bip were elevated after I/R injury. High dosage of resveratrol pretreatment inhibited the injury-induced up-regulation of eIF2 alpha-CHOP and IRE1 alpha-XBP1 pathways. CONCLUSIONS. ER stress is an important contributor to vascular degeneration in retina. Resveratrol suppresses I/R injury and tunicamycin-induced vascular degeneration by inhibiting ER stress. (Invest Ophthalmol Vis Sci. 2012;53:3241-3249) DOI:10.1167/iovs.11-8406