Cited by 207Retinal Diseases and TreatmentsGenomics, phytochemicals, and oxidative stressRetinal Development and Disorders

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Nrf2 signaling is impaired in the aging RPE given an oxidative insult

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Sachdeva, Mira M., Cano, Marisol, Handa, James T.·2014·Experimental Eye Research

DOI 10.1016/j.exer.2013.10.024PMC PMC3946784

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Abstract

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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Background
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BackgroundInfluential
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Background
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Background
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Background
Sialic Acid Mimetic Microglial Sialic Acid-Binding Immunoglobulin-like Lectin Agonism: Potential to Restore Retinal Homeostasis and Regain Visual Function in Age-Related Macular Degeneration
Tolentino, M. J., Tolentino, A. J., Tolentino, E. M., Krishnan, A., & Genead, M. A. (2023) · Pharmaceuticals · doi:10.3390/ph16121735 · Cited by 9
“With age, the production of Nrf2 mRNA and protein decline along with the anti-oxidant response [80].”
Background
Decreased uncoupling protein 2 expression in aging retinal pigment epithelial cells
He, Y., Wang, X., Liu, X., Ji, Z. L., & Ren, Y. (2019) · International Journal of Ophthalmology · doi:10.18240/ijo.2019.03.04 · Cited by 8
AAV NRF2 gene therapy preserves retinal structure and function in rodent models of oxidative damage
Gardner, A., Wang, S., Daniels, A., Li, D. D., Wu, C. C., Lin, L., Hong, C. M., Zhao, S. R., Born, R. T., Kruczek, K., et al. (2026) · Molecular Therapy · doi:10.1016/j.ymthe.2026.02.005 · Cited by 9
“33 There are also dietary compounds touted to be beneficial in aging and a variety of diseases, with effects thought to be mediated by NRF2.”
Sulforaphane recovers cone function in an Nrf2-dependent manner in middle-aged mice undergoing RPE oxidative stress.
Qi, X., Walton, D. A., Plafker, K. S., Boulton, M. E., & Plafker, S. M. (2022) · PubMed Central · Cited by 7
Mitochondrial Dysfunction and Impaired Antioxidant Responses in Retinal Pigment Epithelial Cells Derived from a Patient with RCBTB1-Associated Retinopathy
Huang, Z., Zhang, D., Chen, S., Huang, D., Mackey, D. A., Chen, F. K., & McLenachan, S. (2023) · Cells · doi:10.3390/cells12101358 · Cited by 7
Are Müller glial cells gatekeepers of neuroprotection and regeneration in age-related macular degeneration? Unraveling their roles in pathophysiology and therapeutic innovation
Chen, K.-Y., Chan, H.-C., Hwang, Y., Lin, W., & Chan, C. (2026) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2026.101471 · Cited by 6
Correcting QUEST Magnetic Resonance Imaging–Sensitive Free Radical Production in the Outer Retina In Vivo Does Not Correct Reduced Visual Performance in 24-Month-Old C57BL/6J Mice
Berkowitz, B. A., Podolsky, R. H., Childers, K. L., Roberts, R., Schneider, M., Graffice, E., Sinan, K., Berri, A. M., & Harp, L. (2021) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.62.6.24 · Cited by 6
Simulated microgravity promotes oxidative stress-induced apoptosis in ARPE-19 cells associated with Nrf2 signaling pathway
Huyan, T., Li, M., Chen, W., Zhou, X., Pei, D., Shang, P., & Wu, C. (2022) · Acta Astronautica · doi:10.1016/j.actaastro.2022.05.012 · Cited by 6
APR3 modulates oxidative stress and mitochondrial function in ARPE‐19 cells
Li, Y., Zou, X., Gao, J., Cao, K. J., Feng, Z., & Liu, J. (2018) · The FASEB Journal · doi:10.1096/fj.201800001rr · Cited by 5
“Consistently, Nrf2 mRNA and protein levels have been shown to decline with aging, which renders aging RPE cells vulnerable to oxidative damage (10, 25).”
Background
Age-induced aortic modifications are accompanied by alterations in the antioxidant defense system in female rats
Asad, S. B., Qian, X., Wang, J., Asad, W., Gao, Q., Cao, Y., Huang, Y., Jardan, Y. A. B., Shah, T. A., Wondmie, G. F., et al. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1283302 · Cited by 5
“Surprisingly, the noticeable increase in the basal expressions of NRF2, KEAP-1, and HO-1 proteins in the aorta of aging rats is supported by the findings of others in various organs other than the aorta (41).”
Tetramethylpyrazine protects mice retinas against sodium iodate-induced oxidative injury.
Huang, J., Liu, Y., Mao, K., Gu, Q., & Wu, X. (2020) · PubMed Central · Cited by 5
Newly Identified Chemicals Preserve Mitochondrial Capacity and Decelerate Loss of Photoreceptor Cells in Murine Retinal Degeneration Models
Beeson, C. C., Peterson, Y. K., Perron, N. R., Bandyopadhyay, M., Nasarre, C., Beeson, G. C., Comer, R. F., Lindsey, C. C., Schnellmann, R. G., & Rohrer, B. (2021) · Journal of Ocular Pharmacology and Therapeutics · doi:10.1089/jop.2020.0140 · Cited by 5
“Handa and colleagues have reported that nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is impaired in the aged RPE, 55 and various compounds have been tested for their ability to act as neuroprotectants by upre-gulating Nrf2.”
Lipidomics reveal the protective effects of a vegetable-derived isothiocyanate against retinal degeneration
Kwa, F. A. A., Dulull, N. K., Roessner, U., Dias, D. A., & Rupasinghe, T. (2019) · F1000Research · doi:10.12688/f1000research.19598.2 · Cited by 5
In vitro modeling of the complex retinal condition age-related macular degeneration
Plößl, K., Webster, E., Kiel, C., Graßmann, F., Brandl, C., & Weber, B. H. F. (2022) · Journal of Translational Genetics and Genomics · doi:10.20517/jtgg.2021.39 · Cited by 5
Therapeutic potential of isothiocyanates by targeting the NRF2 pathway
García‐Yagüe, Á. J., Cazalla, E., & Cuadrado, A. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.03.029 · Cited by 5
Fluorescence Lifetime Imaging Ophthalmoscopy of Mouse Models of Age-related Macular Degeneration
Sonntag, S. R., Klein, B., Brinkmann, R., Grisanti, S., & Miura, Y. (2024) · Translational Vision Science & Technology · doi:10.1167/tvst.13.1.24 · Cited by 4
Ilex paraguariensis Extracts Prevent Oxidative Damage in a Mouse Model of Age‐Related Macular Degeneration
Tate, P. S., Marquioni‐Ramella, M. D., Cerchiaro, C., & Suburo, Á. M. (2022) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202100807 · Cited by 4
Urban aerosol particulate matter promotes cellular senescence through mitochondrial ROS-mediated Akt/Nrf2 downregulation in human retinal pigment epithelial cells
Park, B. S., Bang, E., Hwangbo, H., Kim, G., Cheong, J., & Choi, Y. H. (2024) · Free Radical Research · doi:10.1080/10715762.2024.2438919 · Cited by 4
“…in various tissues [35,36]. in particular, sulforaphane has been demonstrated to be effective in aged RPe cells that show impaired Nrf2 signaling [37]. however, the critical role of Nrf2 in UPM-induced RPe cell dysfunction has not yet been demonstrated. in this study, we investigated the…”
Aging of the sensory systems: hearing and vision disorders
Someya, S., & Ikeda, A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-815962-0.00014-7 · Cited by 4
Protrusion of KCNJ13 Gene Knockout Retinal Pigment Epithelium Due to Oxidative Stress–Induced Cell Death
Kanzaki, Y., Fujita, H., Sato, K., Hosokawa, M. M., Matsumae, H., Morizane, Y., & Ohuchi, H. (2022) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.63.12.29 · Cited by 5
Mitigation of Sodium Iodate-Induced Cytotoxicity in Retinal Pigment Epithelial Cells in vitro by Transgenic Erythropoietin-Expressing Mesenchymal Stem Cells
Koh, A. E.-H., Kumar, S. S., Farhana, A., Alam, M. K., & Mok, P. L. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.652065 · Cited by 3
[Retracted] Pinosylvin Extract Retinari™ Sustains Electrophysiological Function, Prevents Thinning of Retina, and Enhances Cellular Response to Oxidative Stress in NFE2L2 Knockout Mice
Tamminen, T., Koskela, A. K. J., Toropainen, E., Gurubaran, I. S., Winiarczyk, M., Liukkonen, M., Paterno, J. J., Lackman, P., Sadeghi, A., Viiri, J., et al. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/8028427 · Cited by 3
Retracted
BlingLife®-Marigold Extract Alleviates Blue Light-Induced Retinal Mitochondria Oxidative Stress and Senescence by Activating NRF2/HO-1 Signaling
Zhou, Z., Li, S., Yang, Q., Zheng, P., & Xie, K. (2025) · Journal of Microbiology and Biotechnology · doi:10.4014/jmb.2411.11037 · Cited by 2
“An existing study has shown that when comparing the RPE cells of aging mice to those of younger mice, NRF2 expression is downregulated, and this downregulation might be associated with an increase in basal oxidative stress with aging [40].”
Nrf2-HO1 signaling pathway-mediated axial elongation in lens-induced myopia in Guinea pigs through regulation of tight junctions in retinal pigment epithelial cells
Li, H., Dong, L., Zhang, R., Zhou, W., Wu, H., Shi, X., Yu, C., Li, Y.-T., Jonas, J. B., & Wei, W. (2025) · Experimental Eye Research · doi:10.1016/j.exer.2025.110477 · Cited by 2
The Mechanism of PMC (2,2,5,7,8-Pentamethyl-6-chromanol), a Sterically Hindered Phenol Antioxidant, in Rescuing Oxidized Low-Density-Lipoprotein-Induced Cytotoxicity in Human Retinal Pigment Epithelial Cells
Chaudhary, S., Moon, J., Hu, Z., Kryukov, E., Pestun, S., Baranov, P. Y., Ng, Y., & D'Amore, P. A. (2025) · Antioxidants · doi:10.3390/antiox14080996 · Cited by 2
“Upon oxidative stress, the dissociation of Nrf2 from its cytoplasmic anchor Kelch-like ECH-associated protein 1 (Keap1) mediates its nuclear translocation and the subsequent transcriptional upregulation of targets of the ARE pathway [16–18].”
Targeting of Nuclear Factor Erythroid 2‐Related Factor 2 (NRF2) Signaling Pathway in Age‐Related Eye Diseases: Molecular Mechanisms and Opportunities for therapy
XinYu, F., Yi, L., & Zg, L. (2026) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.70968 · Cited by 2
“The only way to partially restore Nrf2 signaling in aged RPE was through a conditional knockout of Keap1, the Nrf2 inhibitor [29].”
Lipidomics reveal the protective effects of a vegetable-derived isothiocyanate against retinal degeneration
Kwa, F. A. A., Dulull, N. K., Roessner, U., Dias, D. A., & Rupasinghe, T. (2019) · F1000Research · doi:10.12688/f1000research.19598.1 · Cited by 2
Retinal debris triggers cytotoxic damage in cocultivated primary porcine RPE cells
Wagner, N., Tsai, T., Reinehr, S., Theile, J., Dick, H. B., & Joachim, S. C. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1401571 · Cited by 2
Bioactive peptides alleviating oxidative stress-associated diseases by targeting the Nrf2 signaling pathway
Qin, D., Hu, Z., Han, S., Luo, Y., Yang, F., Xie, T., & Luo, F. (2024) · Food Science and Human Wellness · doi:10.26599/fshw.2024.9250253 · Cited by 2
The oxidative and inflammatory nature of age-related macular degeneration
Torres, R. J. D. A., Torres, R. J. D. A., Luchini, A., & Ferreira, A. L. A. (2022) · Journal of Clinical Ophthalmology and Research · doi:10.4103/jcor.jcor_268_20 · Cited by 2
Lipidomics reveal the protective effects of a vegetable-derived isothiocyanate against retinal degeneration
Kwa, F. A. A., Dulull, N. K., Roessner, U., Dias, D. A., & Rupasinghe, T. (2020) · F1000Research · doi:10.12688/f1000research.19598.3 · Cited by 2
Metabolic reprogramming and mitochondrial dynamics: Novel therapeutic perspectives for age-related macular degeneration
Hu, Z., Qi, H., Dong, X., Tian, Y., Sun, M., Jia, X., & Yu, H. (2026) · Experimental Eye Research · doi:10.1016/j.exer.2026.111064 · Cited by 1
AAV-NRF2 protects retinal and choroidal vasculature in a GDF15-dependent manner in an oxidative damage model of AMD
Wang, S., Zhao, S., Daniels, A., Naaman, E., Gardner, A., Wang, T., Sun, Y., Fu, Z., Smith, L. E. H., & Cepko, C. L. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2616985123 · Cited by 1
“The protection of vessels by either NRF2 overexpression in the RPE, or by addition of GDF15, can be considered in light of AMD pathology.”
Influential
Diseases of the eye
Nesterova, A. P., Климов, Е. А., Zharkova, M., Sozin, S., Sobolev, V. V., Ivanikova, N. V., Shkrob, M., & Yuryev, A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-817086-1.00006-3 · Cited by 1
Animal Models of Diseases of the Retinal Pigment Epithelium
Fletcher, E. L., Greferath, U., Guennel, P., Huynh, M., Findlay, Q. D., Jobling, A. I., Phipps, J. A., Brandli, A. A., Wang, Y. M., Mills, S. A., et al. (2020) · Springer eBooks · doi:10.1007/978-3-030-28384-1_19 · Cited by 1
Лабильность защитной системы клетки Nrf2/Keap/ARE в различных моделях клеточного старения и возрастных патологиях
Шиловский, Г. А. (2022) · Biochemistry (Moscow) · doi:10.31857/s0320972522010067 · Cited by 2
Inhibition of BRD4 Attenuates Inflammation and Oxidative Stress in Retina
Eichenbaum, J. W. (2022) · World Journal of Ophthalmology & Vision Research · doi:10.33552/wjovr.2022.04.000584 · Cited by 1
Systemic Oxidant and Genotoxic Background in Exudative Age-Related Macular Degeneration
Kılıç-Toprak, E., Toprak, İ., Yaylalı, V., Özdemir, Y., Oymak, B., KÜÇÜKATAY, M. B., & Küçükatay, V. (2019) · Süleyman Demirel Üniversitesi Sağlık Bilimleri Dergisi · doi:10.22312/sdusbed.553227
“However, various antioxidant enzymes and defense mechanisms protect the RPE against oxidative damage (9, 20, 21).”
Background
Age-Induced Aortic Modifications Are Accompanied By Alteration in the Antioxidant Defense System in Female RatsPreprint
Asad, S. B., Qian, X., Wang, J., Gao, Q., Cao, Y., Huang, Y., Lu, C., & Zhu, H. F. (2021) · Research Square · doi:10.21203/rs.3.rs-1002842/v1
The nuclear factor E2-related factor 2 and age-related macular degeneration
Torres, R. J. D. A., Torres, R. J. D. A., Luchini, A., & Ferreira, A. L. A. (2022) · Arquivos Brasileiros de Oftalmologia · doi:10.5935/0004-2749.20230024 · Cited by 1
“It has been inferred that reduced Mn-SOD levels are associated with AMD progression (77) .”
Background
Inflammatory potential of diet and aging
Orchard, T., Lohman, M. C., & Kopec, R. E. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-822130-3.00001-6
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Handa, J. T. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-13820-1.00030-x
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Optimized synthesis of 5N-D and the exploration of its role as a promising anti-aging agent via AKR1B1 inhibition and PI3K/Akt/Nrf2 regulation
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Additional file 1 of Protective role of IL-17-producing γδ T cells in a laser-induced choroidal neovascularization mouse model
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Additional file 1 of Artemisinin conferred cytoprotection to human retinal pigment epithelial cells exposed to amiodarone-induced oxidative insult by activating the CaMKK2/AMPK/Nrf2 pathway
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Charles‐Messance, H. (2018) · theses.fr (ABES) · doi:10.70675/674377b7z4bf8z451cz9328zbe6648512747
Retinal pigment epithelium pathology in age-related macular degeneration: mitigation with melatonin
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“…addressed in RPE cells; however, given the numerous studies confirming the stimulatory actions of melatonin on the Nrf2/ARE axis accompanied by the upregulation of antioxidant enzymes in other cells, it is accepted that the same associations exist in the retinal pigment cells (233, 234).”

Authors: Sachdeva, M. M., Cano, M., & Handa, J. T.
Affiliations: Johns Hopkins University (US)
Corresponding author: Handa, James T.
ORCID: Sachdeva, Mira M.
Handa, James T.
Venue: Experimental Eye Research
Publisher: Elsevier BV
Published: 2014-02
Volume: 119
Pages: 111-114
ISSN: 0014-4835 (ISSN-L)
DOI: 10.1016/j.exer.2013.10.024
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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Nrf2 signaling is impaired in the aging RPE given an oxidative insult

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