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Author Do, Ji Yeon ♦ Choi, Young Keun ♦ Kook, Hyun ♦ Suk, Kyoungho ♦ Lee, In-Kyu ♦ Park, Dong Ho
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ ANOXIA ♦ ESTROGENS ♦ GANGLIONS ♦ GENES ♦ GROWTH FACTORS ♦ INDUCTION ♦ INJECTION ♦ ISCHEMIA ♦ LAYERS ♦ MESSENGER-RNA ♦ MICE ♦ OXYGEN ♦ PHOSPHATES ♦ PROMOTERS ♦ RECEPTORS ♦ RETINA ♦ STIMULI
Abstract 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% O{sub 2}). 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. - Highlights: • OIR mice exhibited increased ERRγ expression in the ganglion cell layer. • Hypoxia-induced ERRγ expression was observed in retinal ganglion cells. • ERRγ overexpression increased VEGFA expression in retinal ganglion cells. • An ERRγ inverse agonist suppressed VEGFA expression in retinal ganglion cells. • Intravitreal injection of an ERRγ inverse agonist suppressed VEGFA in OIR mice.
ISSN 0006291X
Educational Use Research
Learning Resource Type Article
Publisher Date 2015-05-01
Publisher Place United States
Journal Biochemical and Biophysical Research Communications
Volume Number 460
Issue Number 2


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