title: Angiotensin II type 1 receptor blockade suppresses light-induced neural damage in the mouse retina.
abstract: Exposure to light contributes to the development and progression of retinal degenerative diseases. However, the mechanisms underlying light-induced tissue damage are not fully understood. Here, we examined the role of angiotensin II type 1 receptor (AT1R) signaling, which is part of the renin-angiotensin system, in light-induced retinal damage. Light-exposed Balb/c mice that were treated with the AT1R blockers (angiotensin II receptor blockers; ARBs) valsartan, losartan, and candesartan before and after the light exposure exhibited attenuated visual function impairment, compared to vehicle-treated mice. This effect was dose-dependent and observed across the ARB class of inhibitors. Further evaluation of valsartan showed that it suppressed a number of light-induced retinal effects, including thinning of the photoreceptor cell layer caused by apoptosis, shortening of the photoreceptor cell outer segment, and increased levels of reactive oxygen species (ROS). The role of ROS in retinal pathogenesis was investigated further using the antioxidant N-acetyl-l-cysteine (NAC). Treatment of light-exposed mice with NAC before the light exposure suppressed the visual function impairment and photoreceptor cell histological changes due to apoptosis. Moreover, treatment with valsartan or NAC suppressed the induction of c-fos (a component of the AP-1 transcription factor) and the upregulation of fasl (a proapoptotic molecule whose transcript is regulated downstream of AP-1). Our results suggest that AT1R signaling mediates light-induced apoptosis, by increasing the levels of ROS and proapoptotic molecules in the retina. Thus, AT1R blockade may represent a new therapeutic approach for preventing light-induced retinal neural tissue damage.
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Narimatsu
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: ozawa@a5.keio.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ozawa
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Miyake
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nagai
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008027:Light; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055214:Retinal Photoreceptor Cell Outer Segment / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine; D019808:Losartan; C081643:candesartan; D000111:Acetylcysteine
keywords: Angiotensin II type 1 receptor; Apoptosis; Light; Oxidative stress; Retina