title: The high-mobility group box-1 nuclear factor mediates retinal injury after ischemia reperfusion.
abstract: OBJECTIVE
  High-mobility group protein B1 (Hmgb1) is released from necrotic cells and induces an inflammatory response. Although Hmgb1 has been implicated in ischemia/reperfusion (IR) injury of the brain, its role in IR injury of the retina remains unclear. Here, the authors provide evidence that Hmgb1 contributes to retinal damage after IR.
  
  
  METHODS
  Retinal IR injury was induced by unilateral elevation of intraocular pressure and the level of Hmgb1 in vitreous humor was analyzed 24 hours after reperfusion. To test the functional significance of Hmgb1 release, ischemic or normal retinas were treated with the neutralizing anti-Hmgb1 antibody or recombinant Hmgb1 protein respectively. To elucidate in which cell type Hmgb1 exerts its effect, primary retinal ganglion cell (RGC) cultures and glia RGC cocultures were treated with Hmgb1. To clarify the downstream signaling pathways involved in Hmgb1-induced effects in the ischemic retina, receptor for advanced glycation end products (Rage)-deficient mice (RageKO) were used.
  
  
  RESULTS
  Hmgb1 is accumulated in the vitreous humor 24 hours after IR. Inhibition of Hmgb1 activity with neutralizing antibody significantly decreased retinal damage after IR, whereas treatment of retinas or retinal cells with Hmgb1 induced a loss of RGCs. The analysis of RageKO versus wild-type mice showed significantly reduced expression of proinflammatory genes 24 hours after reperfusion and significantly increased survival of ganglion cell layer neurons 7 days after IR injury.
  
  
  CONCLUSIONS
  These results suggest that an increased level of Hmgb1 and signaling via the Rage contribute to neurotoxicity after retinal IR injury.
authors.affiliation: Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Galina
authors.initials: G
authors.lastname: Dvoriantchikova
authors.forename: Eleut
authors.initials: E
authors.lastname: Hernandez
authors.forename: Jeff
authors.initials: J
authors.lastname: Grant
authors.forename: Andrea Rachelle C
authors.initials: AR
authors.lastname: Santos
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.forename: Dmitry
authors.initials: D
authors.lastname: Ivanov
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D019084:Fluorescent Antibody Technique, Indirect; D024243:HMGB1 Protein / Q000502:physiology*; D058449:Intravitreal Injections; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009457:Neuroglia / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D012164:Retinal Diseases / Q000378:metabolism* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4