title: Upregulation of thioredoxin system via Nrf2-antioxidant responsive element pathway in adaptive-retinal neuroprotection in vivo and in vitro.
abstract: We tested the hypothesis that stress responses mediated by the Nrf2-antioxidant responsive element (ARE) pathway are involved in the initiation of retinal neuroprotection provided by bright-cyclic-light rearing. Albino rats born and raised in dim (5 lux) or bright (400 lux) cyclic light were exposed to damaging light (3000 lux, 6 h). After exposure, the outer nuclear layer thickness and area and the electroretinogram a- and b-wave amplitudes were significantly reduced in the dim-light-reared rats compared to the bright-light-reared rats, demonstrating a light adaptation neuroprotection phenomenon. In bright-cyclic-light-reared rats, the retinal levels of thioredoxin (Trx) (2.4-fold), Trx reductase (TrxR) (2.9-fold), and proteins modified by 4-hydroxynonenal (4-HNE) (1.5-fold) were upregulated by Western blot analyses, and the nuclear translocation of Nrf2 (2.2-fold) and the DNA binding activity of Nrf2, small Maf, and cJun to the ARE were increased as determined by electrophoretic mobility shift assays. In mouse photoreceptor-derived 661W cells, pretreatment with a sublethal dose of 4-HNE protected against H(2)O(2)-induced cell damage. Treatment with 4-HNE upregulated cellular Trx, TrxR, and heme oxygenase-1 (HO-1) levels in addition to DNA binding activity of Nrf2, small Maf, and cJun to the ARE. Downregulation of Nrf2 using RNA interference technology diminished 4-HNE-mediated upregulation of Trx and Trx reductase but did not affect the upregulation of HO-1 by 4-HNE. Cytoprotection by 4-HNE pretreatment against H(2)O(2)-induced cell damage was not observed in 661W cells with a silenced Nrf2 gene. The results suggest that upregulation of the Trx system by 4-HNE via the Nrf2-ARE pathway may be involved in the molecular mechanism of the retinal neuroprotection phenomenon.
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. tanito-oph@umin.ac.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Tanito
authors.forename: Martin-Paul
authors.initials: MP
authors.lastname: Agbaga
authors.forename: Robert E
authors.initials: RE
authors.lastname: Anderson
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D024202:Electrophoretic Mobility Shift Assay; D004596:Electroretinography; D016758:Genes, jun / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D050978:Maf Transcription Factors, Small / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D010786:Photoreceptor Cells / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements / Q000187:drug effects*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D012172:Retinaldehyde / Q000627:therapeutic use*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000528:radiation effects; D015854:Up-Regulation
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D050978:Maf Transcription Factors, Small; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D016877:Oxidants; D013879:Thioredoxins; D004247:DNA; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; D013880:Thioredoxin-Disulfide Reductase; C027576:4-hydroxy-2-nonenal; D012172:Retinaldehyde