title: Retinal hypoxia induces vascular endothelial growth factor through induction of estrogen-related receptor γ.
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% 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.
authors: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University School of Medicine, Kyungpook National University, Daegu, South Korea.
authors: Ji Yeon
authors: JY
authors: Do
authors: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University School of Medicine, Kyungpook National University, Daegu, South Korea.
authors: Young Keun
authors: YK
authors: Choi
authors: Department of Pharmacology, Chonnam National University Medical School, Gwangju, South Korea.
authors: Hyun
authors: H
authors: Kook
authors: Department of Pharmacology, Brain Science & Engineering Institute, Kyungpook National University School of Medicine, Daegu, South Korea.
authors: Kyoungho
authors: K
authors: Suk
authors: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University School of Medicine, Kyungpook National University, Daegu, South Korea; Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, South Korea.
authors: In-Kyu
authors: IK
authors: Lee
authors: Department of Ophthalmology, Kyungpook National University School of Medicine, Daegu, South Korea. Electronic address: sarasate2222@gmail.com.
authors: Dong Ho
authors: DH
authors: Park
mesh_terms: D000818:Animals; D002460:Cell Line; D000860:Hypoxia / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011960:Receptors, Estrogen / Q000096:biosynthesis*; D012160:Retina / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: C490916:Esrrg protein, mouse; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A
keywords: ERRγ; Ischemic retinopathy; VEGF