期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 42, 期 12, 页码 1838-1850出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2007.03.018
关键词
retinal light adaptation; 4-hydroxynonenal (4-HNE); nuclear-factor-E2-related factor 2 (Nrf2); thioredoxin; thioredoxin reductase; heme oxygenase-1 (HO-1)
资金
- NCRR NIH HHS [RR17703] Funding Source: Medline
- NEI NIH HHS [EY12190, EY04149, EY00871, P30 EY012190] Funding Source: Medline
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 H2O2-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 4-1-HNE-triediated upregulation of Trx and Trx reductase but did not affect the upregulation of HO-1 by 4-HNE. Cytoprotection by 4-HNE pretreatment against H2O2-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. (c) 2007 Elsevier Inc. All rights reserved.
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