A novel AhR ligand, 2AI, protects the retina from environmental stress

• DOI: 10.1038/srep29025
• Publication Date: 2016-07-01T10:50:55Z
• Authors: Mark A. Gutierrez; Sonnet S. Davis; Andrew Rosko; Steven M. Nguyen; Kylie P. Mitchell; Samiha Mateen; Joana Neves; Thelma Y. Garcia; Shaun Mooney; Gary H. Perdew; Troy D. Hubbard; Deepak A. Lamba; Arvind Ramanathan
• Keywords: 0301 basic medicine; 570; Indoles; Polychlorinated Dibenzodioxins; Light; 610; Apoptosis; Retinal Pigment Epithelium; Neurodegenerative; Eye; Inbred C57BL; Small Interfering; Ligands; Protective Agents; Article; Retina; Cell Line; Macular Degeneration; Mice; 03 medical and health sciences; Receptors; Genetics; 2.1 Biological and endogenous factors; Animals; Humans; Aetiology; RNA, Small Interfering; Eye Disease and Disorders of Vision; Inbred BALB C; Ophthalmology and Optometry; Unsaturated; Aldehydes; Mice, Inbred BALB C; Biomedical and Clinical Sciences; Fatty Acids; Neurosciences; 3. Good health; Mice, Inbred C57BL; Receptors, Aryl Hydrocarbon; Aryl Hydrocarbon; Fatty Acids, Unsaturated; RNA; RNA Interference; Lipid Peroxidation; Reactive Oxygen Species; Signal Transduction

Abstract Various retinal degenerative diseases including dry and neovascular age-related macular degeneration (AMD), retinitis pigmentosa, diabetic retinopathy are associated with the of pigmented epithelial (RPE) layer retina. This consequently results in death rod cone photoreceptors that they support, structurally functionally leading to legal or complete blindness. Therefore, developing therapeutic strategies preserve cellular homeostasis RPE would be a favorable asset clinic. The aryl hydrocarbon receptor (AhR) is conserved, environmental ligand-dependent, per ARNT-sim (PAS) domain containing bHLH transcription factor mediates adaptive response stress via its downstream transcriptional targets. Using silico, vitro vivo assays, we identified 2,2′-aminophenyl indole (2AI) as potent synthetic ligand AhR protects cells from lipid peroxidation cytotoxicity mediated by 4-hydroxynonenal (4HNE) well retina light-damage. Additionally, metabolic characterization this molecule LC-MS suggests 2AI alters metabolism cells, enhancing intracellular levels palmitoleic acid. Finally, show that, effector 2AI-mediated activation, acid 4HNE-mediated stress, light mice.