title: Endoplasmic reticulum stress in retinal vascular degeneration: protective role of resveratrol.
abstract: OBJECTIVE
  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 μM 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 2α (eIF2α), CCAAT enhancer-binding protein homologous protein (CHOP), immunoglobulin binding protein (Bip), inositol requiring enzyme 1α (IRE1α), 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 eIF2α, IRE1α, 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 eIF2α-CHOP and IRE1α-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.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Chuanzhou
authors.initials: C
authors.lastname: Li
authors.forename: Leilei
authors.initials: L
authors.lastname: Wang
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.forename: Ling
authors.initials: L
authors.lastname: Zheng
mesh_terms: D020533:Angiogenesis Inhibitors; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D012313:RNA / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D015427:Reperfusion Injury / Q000150:complications; D000077185:Resveratrol; D012162:Retinal Degeneration / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology; D012171:Retinal Vessels / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014415:Tunicamycin / Q000633:toxicity; D015854:Up-Regulation; D000071717:X-Box Binding Protein 1; D051028:bcl-2-Associated X Protein
chemical_list: D020533:Angiogenesis Inhibitors; D000975:Antioxidants; C539791:Bax-inhibiting peptide, BIP; D004268:DNA-Binding Proteins; D009842:Oligopeptides; D000071701:Regulatory Factor X Transcription Factors; D013267:Stilbenes; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D051028:bcl-2-Associated X Protein; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D012313:RNA; D017346:Protein Serine-Threonine Kinases; C531557:eIF2alpha kinase, mouse; D000077185:Resveratrol