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  • br Acknowledgements br Introduction Ischemic retinopathy is

    2020-05-22


    Acknowledgements
    Introduction Ischemic retinopathy is common to the major causes of blindness, including proliferative diabetic retinopathy, venous occlusion, and retinopathy of prematurity. The hypoxia that follows retinal capillary obliteration drives deregulated growth of new blood vessels protruding out of retinal surfaces, without ameliorating retinal ischemia [1], [2], [3]. Under hypoxic conditions, dimerization of the stabilized hypoxia-inducible factor (HIF)-α subunit with the HIF-β subunit enables the transcription of a wide range of pak1 inhibitor including those involved in cellular metabolism, hypoxia tolerance, and angiogenesis, such as vascular endothelial growth factor (VEGF) [4]. VEGF is a potent inducer of vasopermeability and macular edema [5], the leading cause of vision loss in working-age populations. Recently developed treatments using anti-VEGF agents result in the improvement of visual acuity in patients with diabetic macular edema. However, despite the clinically significant benefits of intravitreal injection of anti-VEGF agents, some patients show only a partial response to this therapy, with persistent diabetic macular edema and/or poor visual acuity [6]. Thus, understanding the pathophysiology of ischemic retinopathy and identifying potentially 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 [7], [8], [9]. ERRγ, like other members of the ERR subfamily, is a constitutively active orphan nuclear receptor. It is selectively expressed in metabolically active tissues such as skeletal muscle, liver, brain, and retina [10], [11], [12], [13]. In liver cell lines, mRNA and protein levels of ERRγ are increased by hypoxia or desferrioxamine (DFO) treatment, and HIF-1α mediates the induction of ERRγ under hypoxic conditions [14]. The retina is a neural tissue with high metabolic activity and the highest oxygen consumption per unit weight of any human tissue [15]. However, the role of ERRγ in the retina, particularly in regulating VEGF in ischemic retinopathy, has not been studied. GSK5182, a 4-hydroxytamoxifen analog, is a highly selective inverse agonist of ERRγ and does not interact with any other nuclear receptors, including ERRα, due to its non-covalent interactions with Y326 and N346 at the active site of ERRγ [16], [17].
    Material and methods
    Results and discussion
    Conflict of interest
    Acknowledgments This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2014R1A1A2055007) and by the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111345).