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.