Ischemic retinopathies causing overexpression of pro-angiogenic factors, including
vascular endothelial growth factor (
VEGF), are the most common cause of
blindness. Thus, understanding the pathophysiology of targetable pathways that regulate
retinal VEGF is of great interest. A conserved binding site for
estrogen-related receptor γ (ERRγ) has been identified in the promoter of the Vegfa gene. ERRγ is a constitutively active
orphan nuclear receptor and its expression is increased by hypoxic stimuli in metabolically active tissues. This study evaluated the role of ERRγ in the ischemic retina and the anti-
VEGF potential of
GSK5182, a selective inverse agonist of ERRγ. In an
oxygen-induced retinopathy (OIR) mouse model, immunohistochemistry showed significantly increased ERRγ expression in the
ganglion cell layer at postnatal day (P) 17. In a
ganglion cell line (RGC-5),
mRNA and
protein levels of ERRγ were increased by
desferrioxamine treatment and hypoxic conditions (1% O2). Transient transfection of RGC-5 cells revealed that ERRγ regulated Vegfa expression and this was inhibited by
GSK5182.
Intravitreal injection of
GSK5182 into the OIR model at P14 inhibited
retinal Vegfa
mRNA expression at P17.
GSK5182 suppresses
hypoxia-induced
VEGF expression via ERRγ; therefore, ERRγ could be a treatment target for ischemic retinopathies.