title: A novel AhR ligand, 2AI, protects the retina from environmental stress.
abstract: 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.
authors.affiliation: University of Denver, Colorado 2199 S University Blvd, Denver, CO 80208, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gutierrez
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94901, USA.
authors.forename: Sonnet S
authors.initials: SS
authors.lastname: Davis
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94901, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rosko
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94901, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Nguyen
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94901, USA.
authors.forename: Kylie P
authors.initials: KP
authors.lastname: Mitchell
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94901, USA.
authors.forename: Samiha
authors.initials: S
authors.lastname: Mateen
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94901, USA.
authors.forename: Joana
authors.initials: J
authors.lastname: Neves
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94901, USA.
authors.forename: Thelma Y
authors.initials: TY
authors.lastname: Garcia
authors.affiliation: University of Washington Box 358047 Seattle, WA 98195, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Mooney
authors.affiliation: The Pennsylvania State University, Center for Molecular Toxicology and Carcinogenesis, 309 Life Sciences Building, University Park, PA 16802, USA.
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
authors.affiliation: The Pennsylvania State University, Center for Molecular Toxicology and Carcinogenesis, 309 Life Sciences Building, University Park, PA 16802, USA.
authors.forename: Troy D
authors.initials: TD
authors.lastname: Hubbard
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94901, USA.
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Lamba
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94901, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Ramanathan
mesh_terms: D000447:Aldehydes / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008027:Light; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000737:chemistry / Q000633:toxicity; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000447:Aldehydes; D005231:Fatty Acids, Unsaturated; D007211:Indoles; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D020011:Protective Agents; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; C027576:4-hydroxy-2-nonenal