title: Role of endoplasmic reticulum stress in light-induced photoreceptor degeneration in mice.
abstract: Exposure to excessive levels of light induces photoreceptor apoptosis and can be a causative factor in age-related macular degeneration (AMD). However, the cellular events that mediate this apoptotic response are poorly understood. Here, we investigated the roles of endoplasmic reticulum (ER) stress in light-induced cell death in the murine retina and murine photoreceptor cells (661W). Excessive light exposure induced retinal dysfunction, photoreceptor degeneration, and apoptosis. Furthermore, the accumulation of polyubiquitinated proteins and the transcriptional expression of ER stress-related factors, including 78-kDa glucose-regulated protein (GRP78)/immunoglobulin-binding protein (BiP) and C/EBP-homologous protein (CHOP), were increased in light-exposed retinas. Light exposure also induced both cell death and up-regulation of polyubiquitinated proteins, S-opsin aggregation, bip and chop mRNAs in 661W cells in vitro. Knock-down of chop mRNA inhibited photoreceptor cell death induced by light exposure. Furthermore, treatment with BiP inducer X (BIX), an ER stress inhibitor, induced bip mRNA and reduced both chop expression and light-induced photoreceptor cell death. These data indicate that excessive ER stress may induce photoreceptor cell death in light-exposed retinas via activation of the CHOP-dependent apoptotic pathway, suggesting that the ER stress may play a pivotal role in light exposure-induced retinal damage.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Sou
authors.initials: S
authors.lastname: Sugitani
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudo
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Imai
authors.forename: Yuta
authors.initials: Y
authors.lastname: Inokuchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008027:Light / Q000009:adverse effects*; D008297:Male; D051379:Mice; D055355:Opsins / Q000378:metabolism; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology / Q000528:radiation effects*; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000473:pathology / Q000528:radiation effects*; D013861:Thiocyanates / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics; D054875:Ubiquitination
chemical_list: C527742:1-(3,4-dihydroxyphenyl)-2-thiocyanate-ethanone; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D055355:Opsins; D012333:RNA, Messenger; D013861:Thiocyanates; D051742:Transcription Factor CHOP