title: Angiopoietin 2 induces astrocyte apoptosis via αvβ5-integrin signaling in diabetic retinopathy.
abstract: The vascular leakage in diabetic retinopathy leads to macular edema and vision loss. Although astrocyte play an important role in regulating blood-brain barrier integrity in the brain, the precise role of astrocyte in blood-retinal barrier was yet to be elucidated. This study aimed to investigate the role of angiopoietin 2 (Ang2) in astrocyte loss and vascular leakage in the early streptozotocin-induced diabetic retinopathy. We demonstrated that vascular leakage occurred with astrocyte loss in early diabetic mice retina as Ang2 increased. The astrocyte loss and vascular leakage were inhibited by intravitreal injection of Ang2-neutralizing antibody. In vitro, Ang2 aggravated high glucose-induced astrocyte apoptosis via GSK-3β activation. Ang2 directly bound to αvβ5 integrin, which was abundant in astrocyte, and the blockade of αvβ5 integrin, in vitro, effectively attenuated Ang2-induced astrocyte apoptosis. In vivo, intravitreal injection of anti-αvβ5-integrin antibody inhibited astrocyte loss in early diabetic retinopathy. Taken together, Ang2 induced astrocyte apoptosis under high glucose via αvβ5-integrin/GSK-3β/β-catenin pathway. Therefore, we suggest that Ang2/integrin signaling could be a potential therapeutic target to prevent the vascular leakage by astrocyte loss in early diabetic retinopathy.
authors.affiliation: Department of Pharmacology and Ischemic/Hypoxic Disease Institute and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Yun
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.|Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Biomedical Research Institute, Seoul National University Hospital, and Department of Biomedical Sciences and Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: S W
authors.initials: SW
authors.lastname: Park
authors.affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Biomedical Research Institute, Seoul National University Hospital, and Department of Biomedical Sciences and Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Ischemic/Hypoxic Disease Institute and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: C-H
authors.initials: CH
authors.lastname: Cho
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.|Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Biomedical Research Institute, Seoul National University Hospital, and Department of Biomedical Sciences and Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D003930:Diabetic Retinopathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019030:Receptors, Vitronectin / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D042702:Angiopoietin-2; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; C064660:integrin alphaVbeta5