The DOI matches its Crossref record; 18 of the 18 references it cites were found in a registry or an index.
Nrf2 signaling is impaired in the aging RPE given an oxidative insult
Open accessAbstract
Age-related macular degeneration (AMD) represents the leading cause of blindness in the elderly, yet no definitive therapy exists for early, dry disease. Several lines of evidence have implicated oxidative stress-induced damage to the retinal pigment epithelium (RPE) in the pathogenesis of AMD, suggesting that the aging RPE may exhibit increased susceptibility to cell damage induced by exogenous stressors. The transcription factor Nrf2 serves as the master regulator of a highly coordinated antioxidant response in virtually all cell types. We compared Nrf2 signaling in the RPE of young (2 months) and old (15 months) mice under unstressed and stressed (sodium iodate) conditions. The aging RPE expressed higher levels of the Nrf2 target genes NQO1, GCLM, and HO1 compared with the RPE of younger mice under unstressed conditions, suggesting an age-related increase in basal oxidative stress. Moreover, the RPE of older mice demonstrated impaired induction of the protective Nrf2 pathway following oxidative stress induced with sodium iodate. The RPE of old mice exposed to sodium iodate also exhibited higher levels of superoxide anion and malondialdehyde than young mice, suggesting inadequate protection against oxidative damage. Induction of Nrf2 signaling in response to sodium iodate was partially restored in the RPE of aging mice with genetic rescue, using conditional knockdown of the Nrf2 negative regulator Keap1 (Tam-Cre; Keap1loxP) compared to Keap1loxP mice. These data indicate that the aging RPE is vulnerable to oxidative damage due to impaired Nrf2 signaling, and that Nrf2 signaling is a promising target for novel pharmacologic or genetic therapeutic strategies.
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“Nrf2 signaling has been found to decrease with age [207] in a variety of model organisms including flies [208], mice [209], non-human primates [210,211], and humans [207,212,213,214].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [209]
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Citations
Cites
Prevalence of Age-Related Macular Degeneration in the United States
The Eye Diseases Prevalence Research Group* (2004) · Archives of Ophthalmology · doi:10.1001/archopht.122.4.564 · Cited by 2,774 · cited 1×
“Moreover, as the population continues to age, the prevalence of AMD is projected to double over a 20-year period, increasing to 2.95 million by 2020 (Friedman et al., 2004).”
InfluentialCauses and Prevalence of Visual Impairment Among Adults in the UnitedStates
(2004) · Archives of Ophthalmology · doi:10.1001/archopht.122.4.477 · Cited by 2,616 · cited 1×
“Age-relatedmacular degeneration (AMD) represents the leading cause of vision impairment in the elderly, accounting for 54% of blindness in Caucasian Americans (Congdon et al., 2004).”
Mechanistic Studies of the Nrf2-Keap1 Signaling Pathway
Zhang, D. D. (2006) · Drug Metabolism Reviews · doi:10.1080/03602530600971974 · Cited by 1,105 · cited 2×
“However, under conditions of oxidative stress, Keap1 undergoes a conformational modification and releases Nrf2 for translocation to the nucleus where it binds to antioxidant response elements (AREs), thus activating transcription of its target genes, including glutamate cysteine ligase modifier subunit (GCLM), heme ox…”
Risk factors for age-related macular degeneration
Smith, W., Assink, J., Klein, R., Mitchell, P., Klaver, C. C. W., Klein, B. E. K., Hofman, A., Jensen, S., Wang, J. J., & de Jong, P. T. V. M. (2001) · Ophthalmology · doi:10.1016/s0161-6420(00)00580-7 · Cited by 1,071 · cited 3×
“…studies, cigarette smoking, a powerful chemical oxidant, is the most strongly linked modifiable risk factor, with a direct association between pack-years and prevalence of geographic atrophy or CNV(Khan et al., 2006; Smith et al., 2001; t., Wilmer Ophthalmological , Baltimore, MD 21287, USA.”
Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation
Wakabayashi, N., Itoh, K., Wakabayashi, J., Motohashi, H., Noda, S., Takahashi, S., Imakado, S., KOTSUJI, T., Otsuka, F., Roop, D. R., et al. (2003) · Nature Genetics · doi:10.1038/ng1248 · Cited by 881 · cited 1×
“Since Global Keap1 deficient mice are embryologically lethal (Wakabayashi et al., 2003), we used tamoxifen inducible Cre recombinase (Tam-Cre) mice that were crossed with floxed keap1 (Keap1loxP) mice to generate inducible Keap1 knockout mice (Tam-Cre; Keap1loxP).”
Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., O'Connor, T., & Yamamoto, M. P. (2003) · Genes to Cells · doi:10.1046/j.1365-2443.2003.00640.x · Cited by 828 · cited 2×
“…with the release of the Nrf2 protein from cytosolic Keap1 to allow for nuclear translocation and the initiation of the cytoprotective response via binding to AREs, with minimal variable direct effects on Nrf2 transcription (Braun et al., 2002; Itoh et al., 2003; Vargas et al., 2005).”
Risk factors for incident age-related macular degeneration
Tomany, S. C., Wang, J. J., van Leeuwen, R., Klein, R., Mitchell, P., Vingerling, J. R., Klein, B. E. K., Smith, W., & de Jong, P. T. V. M. (2004) · Ophthalmology · doi:10.1016/j.ophtha.2003.11.010 · Cited by 621 · cited 1×
“Tomany et al., 2004).”
Complement factor H binds malondialdehyde epitopes and protects from oxidative stress
Weismann, D., Hartvigsen, K., Lauer, N., Bennett, K. L., Scholl, H. P. N., Issa, P. C., Cano, M., Brandstätter, H., Tsimikas, S., Skerka, C., et al. (2011) · Nature · doi:10.1038/nature10449 · Cited by 533 · cited 1×
“To establish whether these levels of superoxide anion were associated with oxidative damage to the RPE, we performed immunolabeling for malondialdehyde (MDA), a known lipid peroxidation product that has been identified in AMD (Weismann et al., 2011).”
Rosenfeld, M. E., Palinski, W., Ylä‐Herttuala, S., Butler, S. S., & Witztum, J. L. (1990) · Arteriosclerosis An Official Journal of the American Heart Association Inc · doi:10.1161/01.atv.10.3.336 · Cited by 474 · cited 2×
“Sections were then incubated with MDA2, a murine IgG monoclonal antibody that binds tomalondialdehyde (MDA)-lysine epitopes present on modified LDL or other MDA-modified proteins but not to native LDL or unmodified proteins (Courtesy, J Witztum,MD, UC San Diego (Rosenfeld et al., 1990)), overnight at 4 C, washed with…”
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Łoboda, A., Damulewicz, M., Pyza, E., Józkowicz, A., & Dulak, J. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2223-0 · Cited by 2,709
“The direct comparison of young (2 months) and old (15 months) mice under unstressed and sodium iodatestressed conditions, that is the frequently used model for the retinal degeneration [180], have underlined the involvement of Nrf2 signaling in the pathogenesis of the disease [181].”
BackgroundNrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease
Ngo, V., & Duennwald, M. L. (2022) · Antioxidants · doi:10.3390/antiox11122345 · Cited by 1,130
The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD
Datta, S., Cano, M., Ebrahimi, K. B., Wang, L., & Handa, J. T. (2017) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.03.002 · Cited by 843
“Our lab has shown that aging impaired the Nrf2 response in the RPE after acute oxidative stress in mice (Sachdeva et al., 2014).”
BackgroundOxidative stress response and Nrf2 signaling in aging
Zhang, H., Davies, K. J. A., & Forman, H. J. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.05.036 · Cited by 804
“On the other hand, a recent study showed that Keap1 knockout partially restored the induction of NQO-1, whose induction was impaired in the retinal pigment epithelium of middle-aged mice (15 mo), while the induction of HO-1 and GCLM was not recovered [158].”
The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging
Yu, C., & Xiao, J.-H. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6635460 · Cited by 537
“Nrf2 signaling was impaired in the retinal pigment epithelium in aging mice [32].”
Background
Metadata
- Authors
- Sachdeva, M. M., Cano, M., & Handa, J. T.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Handa, James T.
- Venue
- Experimental Eye Research
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 119
- Pages
- 111-114
- ISSN
- 0014-4835 (ISSN-L)
- PMC
- PMC3946784
- OpenAlex
- W2036704550
- Cited by
- 207
- References
- 18
- Citations by year
- 2026: 13 · 2025: 8 · 2024: 15 · 2023: 22 · 2022: 28 · 2021: 25 · 2020: 29 · 2019: 21 · 2018: 10 · 2017: 13 · 2016: 13 · 2015: 8 · 2014: 2
- FWCI
- 7.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Experimental Eye Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NEI (EY019904, EY14005)
- Thome Foundation Award in AMD
- RPB Senior Scientist Award
- Wilmer Core Grant (EY001765)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Keywords
- Nrf2 signaling, retinal pigment epithelium, aging, age-related macular degeneration, oxidative stress, sodium iodate, Keap1, antioxidant response, NQO1, GCLM, heme oxygenase-1, superoxide, malondialdehyde, genetic rescue
- MeSH terms
- Aging, Animals, Humans, Macular Degeneration, Signal Transduction, Oxidative Stress, NF-E2-Related Factor 2, Retinal Pigment Epithelium
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