TY - JOUR
T1 - Oxidative stress induces an interactive decline in Wnt and Nrf2 signaling in degenerating retinal pigment epithelium
AU - Ebrahimi, Katayoon B.
AU - Cano, Marisol
AU - Rhee, John
AU - Datta, Sayantan
AU - Wang, Lei
AU - Handa, James T.
N1 - Funding Information:
We thank Stephen Chan, Sonny Dike, Natalia Vergara, Christian Gutierrez, and Gillian Shaw for their technical expertise and guidance, and Akrit Sodhi, MD, PhD, and Debasish Sinha, PhD, for carefully critiquing the article. We thank Victor Perez, MD, for providing CEP-BSA. Supported by the NIH EY019904 (J.T.H.), EY14005 (J.T.H.), EY027691 (J.T.H.), EY 01765 (Wilmer Imaging Core grant), K12 EY108198 (K.B.E.), RPB Senior Scientist Award ( J.T.H.), unrestricted grant from RBP, and gifts from the Merlau family and Aleda Wright.
Publisher Copyright:
© Copyright 2018, Mary Ann Liebert, Inc. 2018.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - Aims: Cells have evolved a highly sophisticated web of cytoprotective systems to neutralize unwanted oxidative stress, but are challenged by unique modern day stresses such as cigarette smoking and ingestion of a high-fat diet (HFD). Age-related disease, such as age-related macular degeneration (AMD), the most common cause of blindness among the elderly in Western societies, develops in part, when oxidative stress overwhelms cytoprotective systems to injure tissue. Since most studies focus on the protection by a single protective system, the aim of this study was to investigate the impact of more than one cytoprotective system against oxidative stress. Results: Wingless (Wnt) and nuclear factor-erythroid 2-related factor 2 (Nrf2), two fundamental signaling systems that are vital to cell survival, decline after mice are exposed to chronic cigarette smoke and HFD, two established AMD risk factors, in a bidirectional feedback loop through phosphorylated glycogen synthase kinase 3 beta. Decreased Wnt and Nrf2 signaling leads to retinal pigment epithelial dysfunction and apoptosis, and a phenotype that is strikingly similar to geographic atrophy (GA), an advanced form of AMD with no effective treatment. Innovation: This study is the first to show that chronic oxidative stress from common modern day environmental exposures reduces two fundamental and vital cytoprotective networks in a bidirectional feedback loop, and their decline leads to advanced disease phenotype. Conclusion: Our data offer new insights into how combined modern oxidative stresses of cigarette smoking and HFD contribute to GA through an interactive decline in Wnt and Nrf2 signaling. Antioxid. Redox Signal. 29, 389-407.
AB - Aims: Cells have evolved a highly sophisticated web of cytoprotective systems to neutralize unwanted oxidative stress, but are challenged by unique modern day stresses such as cigarette smoking and ingestion of a high-fat diet (HFD). Age-related disease, such as age-related macular degeneration (AMD), the most common cause of blindness among the elderly in Western societies, develops in part, when oxidative stress overwhelms cytoprotective systems to injure tissue. Since most studies focus on the protection by a single protective system, the aim of this study was to investigate the impact of more than one cytoprotective system against oxidative stress. Results: Wingless (Wnt) and nuclear factor-erythroid 2-related factor 2 (Nrf2), two fundamental signaling systems that are vital to cell survival, decline after mice are exposed to chronic cigarette smoke and HFD, two established AMD risk factors, in a bidirectional feedback loop through phosphorylated glycogen synthase kinase 3 beta. Decreased Wnt and Nrf2 signaling leads to retinal pigment epithelial dysfunction and apoptosis, and a phenotype that is strikingly similar to geographic atrophy (GA), an advanced form of AMD with no effective treatment. Innovation: This study is the first to show that chronic oxidative stress from common modern day environmental exposures reduces two fundamental and vital cytoprotective networks in a bidirectional feedback loop, and their decline leads to advanced disease phenotype. Conclusion: Our data offer new insights into how combined modern oxidative stresses of cigarette smoking and HFD contribute to GA through an interactive decline in Wnt and Nrf2 signaling. Antioxid. Redox Signal. 29, 389-407.
KW - Nrf2
KW - Wnt
KW - age-related macular degeneration
KW - aging
KW - high-fat diet
KW - oxidative stress
KW - smoking
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U2 - 10.1089/ars.2017.7084
DO - 10.1089/ars.2017.7084
M3 - Article
C2 - 29186981
AN - SCOPUS:85049346619
SN - 1523-0864
VL - 29
SP - 389
EP - 407
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 4
ER -