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

Various retinal degenerative diseases including dry and neovascular age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy are associated with the degeneration of the retinal pigmented epithelial (RPE) layer of the retina. This consequently results in the death of rod...

Full description

Saved in:

Bibliographic Details
Published in:	Scientific reports Vol. 6; no. 1; p. 29025
Main Authors:	Gutierrez, Mark A., Davis, Sonnet S., Rosko, Andrew, Nguyen, Steven M., Mitchell, Kylie P., Mateen, Samiha, Neves, Joana, Garcia, Thelma Y., Mooney, Shaun, Perdew, Gary H., Hubbard, Troy D., Lamba, Deepak A., Ramanathan, Arvind
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-07-2016 Nature Publishing Group
Subjects:	13/1 42/47 631/92/320 631/92/613 64/60 Aldehydes - toxicity Animals Apoptosis - drug effects Cell Line Cytochrome Cytotoxicity Dioxins Environmental stress Fatty Acids, Unsaturated - metabolism Homeostasis Humanities and Social Sciences Humans Hydrocarbons Indoles - chemistry Indoles - pharmacology Ligands Light Lipid Peroxidation - drug effects Localization Macular degeneration Mice Mice, Inbred BALB C Mice, Inbred C57BL multidisciplinary Oxidation Peroxidation Photoreceptors Polychlorinated Dibenzodioxins - chemistry Polychlorinated Dibenzodioxins - toxicity Protective Agents - chemistry Protective Agents - pharmacology Reactive Oxygen Species - metabolism Receptors, Aryl Hydrocarbon - antagonists & inhibitors Receptors, Aryl Hydrocarbon - genetics Receptors, Aryl Hydrocarbon - metabolism Retina Retina - drug effects Retina - metabolism Retina - pathology Retina - radiation effects Retinal Pigment Epithelium - cytology Retinal Pigment Epithelium - drug effects Retinal Pigment Epithelium - metabolism RNA Interference RNA, Small Interfering - metabolism Science Science (multidisciplinary) Signal Transduction - drug effects Transcription factors
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Various retinal degenerative diseases including dry and neovascular age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy are associated with the degeneration of the retinal pigmented epithelial (RPE) layer of the retina. This consequently results in the death of rod and cone photoreceptors that they support, structurally and functionally leading to legal or complete blindness. Therefore, developing therapeutic strategies to preserve cellular homeostasis in the RPE would be a favorable asset in the clinic. The aryl hydrocarbon receptor (AhR) is a conserved, environmental ligand-dependent, per ARNT-sim (PAS) domain containing bHLH transcription factor that mediates adaptive response to stress via its downstream transcriptional targets. Using in silico, in vitro and in vivo assays, we identified 2,2′-aminophenyl indole (2AI) as a potent synthetic ligand of AhR that protects RPE cells in vitro from lipid peroxidation cytotoxicity mediated by 4-hydroxynonenal (4HNE) as well as the retina in vivo from light-damage. Additionally, metabolic characterization of this molecule by LC-MS suggests that 2AI alters the lipid metabolism of RPE cells, enhancing the intracellular levels of palmitoleic acid. Finally, we show that, as a downstream effector of 2AI-mediated AhR activation, palmitoleic acid protects RPE cells from 4HNE-mediated stress, and light mediated retinal degeneration in mice.
ISSN:	2045-2322 2045-2322
DOI:	10.1038/srep29025