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We postulated that dh404, an activator of nuclear factor erythroid-2 related factor 2 (Nrf2), the master regulator of oxidative stress responses, would attenuate retinal vasculopathy by mechanisms involving protection against oxidative stress-mediated damage to glia. Oxygen-induced retinopathy (OIR) was induced in neonatal C57BL\/6J mice by exposure to hyperoxia (phase I) followed by room air (phase II). dh404 (1\u00a0mg\/kg\/every second day) reduced the vaso-obliteration of phase I OIR and neovascularization, vascular leakage and inflammation of phase II OIR. In phase I, the astrocytic template and vascular endothelial growth factor (VEGF) expression necessary for physiological angiogenesis are compromised resulting in vaso-obliteration. These events were attenuated by dh404 and related to dh404\u2019s ability to reduce the hyperoxia-induced increase in reactive oxygen species (ROS) and markers of cell damage as well as boost the Nrf2-responsive antioxidants in cultured astrocytes. In phase II, neovascularization and vascular leakage occurs following gliosis of M\u00fcller cells and their subsequent increased production of angiogenic factors. dh404 reduced M\u00fcller cell gliosis and vascular leakage in OIR as well as the hypoxia-induced increase in ROS and angiogenic factors with a concomitant increase in Nrf2-responsive antioxidants in cultured M\u00fcller cells. In conclusion, agents such as dh404 that reduce oxidative stress and promote antioxidant capacity offer a novel approach to lessen the vascular and glial cell damage that occurs in ischaemic retinopathies.<\/jats:p>","DOI":"10.1042\/cs20160068","type":"journal-article","created":{"date-parts":[[2016,3,23]],"date-time":"2016-03-23T03:05:17Z","timestamp":1458702317000},"page":"1375-1387","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["A potent Nrf2 activator, dh404, bolsters antioxidant capacity in glial cells and attenuates ischaemic retinopathy"],"prefix":"10.1042","volume":"130","author":[{"given":"Devy","family":"Deliyanti","sequence":"first","affiliation":[{"name":"Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae\u00a0Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Petratos","sequence":"additional","affiliation":[{"name":"Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin\u00a0J.","family":"Meyer","sequence":"additional","affiliation":[{"name":"Reata Pharmaceuticals Inc. 2801 Gateway Dr, Irving, TX 75063, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith\u00a0W.","family":"Ward","sequence":"additional","affiliation":[{"name":"Reata Pharmaceuticals Inc. 2801 Gateway Dr, Irving, TX 75063, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer\u00a0L.","family":"Wilkinson-Berka","sequence":"additional","affiliation":[{"name":"Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy\u00a0B.","family":"de Haan","sequence":"additional","affiliation":[{"name":"Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia"},{"name":"Reata Pharmaceuticals Inc. 2801 Gateway Dr, Irving, TX 75063, U.S.A."},{"name":"Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2016,6,29]]},"reference":[{"key":"2021113010425647400_B1","first-page":"1162","article-title":"Mechanisms and management of retinopathy of prematurity","volume":"368","author":"Hartnett","year":"2013","journal-title":"N. 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