title: A potent Nrf2 activator, dh404, bolsters antioxidant capacity in glial cells and attenuates ischaemic retinopathy.
abstract: An imbalance in oxidative stress and antioxidant defense mechanisms contributes to the development of ischaemic retinopathies such as diabetic retinopathy and retinopathy of prematurity (ROP). Currently, the therapeutic utility of targeting key transcription factors to restore this imbalance remains to be determined. 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 mg/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's 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 Müller cells and their subsequent increased production of angiogenic factors. dh404 reduced Müller 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 Müller 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.
authors.affiliation: Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Devy
authors.initials: D
authors.lastname: Deliyanti
authors.affiliation: Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Petratos
authors.affiliation: Reata Pharmaceuticals Inc. 2801 Gateway Dr, Irving, TX 75063, U.S.A.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Meyer
authors.affiliation: Reata Pharmaceuticals Inc. 2801 Gateway Dr, Irving, TX 75063, U.S.A.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Ward
authors.affiliation: Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia judy.dehaan@bakeridi.edu.au jennifer.wilkinson-berka@monash.edu.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wilkinson-Berka
authors.affiliation: Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia Reata Pharmaceuticals Inc. 2801 Gateway Dr, Irving, TX 75063, U.S.A. Oxidative Stress Laboratory, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia judy.dehaan@bakeridi.edu.au jennifer.wilkinson-berka@monash.edu.
authors.forename: Judy B
authors.initials: JB
authors.lastname: de Haan
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D063928:Ependymoglial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018496:Hyperoxia / Q000150:complications; D018836:Inflammation Mediators / Q000378:metabolism; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015861:Retinal Neovascularization / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012178:Retinopathy of Prematurity / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D042501:Angiogenic Proteins; D000975:Antioxidants; D016207:Cytokines; D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C495637:Nfe2l2 protein, rat; C547749:dh404 compound; D009828:Oleanolic Acid
keywords: antioxidants; glia; neovascularization; retinopathy; vasculopathy