Cited by 163Advanced Glycation End Products researchChronic Kidney Disease and DiabetesNitric Oxide and Endothelin Effects

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Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor

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Cai, Weijing, He, John C., Zhu, Li, Lu, Changyong, Vlassara, Helen·2006·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0600362103PMC PMC1564251

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Abstract

Advanced glycation end product receptors (AGERs) play distinct functional roles in both the toxicity and disposal of advanced glycation end products (AGEs), substances that are linked to diabetes and aging. Overexpression of AGER1 in murine mesangial cells (MCs) (MC-R1) inhibited AGE-induced MAPK1,2 phosphorylation and NF-kappaB activity and also increased AGE degradation. The mechanism of the inhibitory effects of AGER1, upstream of MAPK, was explored in MCs and HEK293 AGER1-expressing cells. AGE-induced Ras activation was found to be linked to Shc/Grb2 complex formation and Shc phosphorylation in MCs, responses that were markedly reduced in MC-R1 cells. AGE responses also included EGF receptor (EGFR) phosphorylation in MCs or HEK293 cells, but this link was blocked in both MC-R1 and HEK293-R1 cells. Coexpression of AGER1 and EGFR in HEK293 cells decreased AGE-mediated EGFR and p44/p42 phosphorylation but not EGF-induced p44/p42 activation. AGE, S100/calgranulin, or H(2)O(2) promoted MAPK phosphorylation in EGFR(+) cells in a manner that was inhibitable by an EGFR inhibitor, AG1478. Also, in AGER1 cells, AGE-induced H(2)O(2) formation and AGE- or S100-induced p44/p42 phosphorylation were suppressed, and these effects were restored by R1 siRNA. These data confirm that R1 negatively regulates AGE-mediated oxidant stress-dependent signaling via the EGFR and Shc/Grb2/Ras pathway. AGER1 could serve as a model for developing therapeutic targets against vascular and kidney disorders related to diabetes and aging.

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Authors: Cai, W., He, J. C., Zhu, L., Lu, C., & Vlassara, H.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029
*Division of Experimental Diabetes and Aging, Brookdale Department of Geriatrics, and
Corresponding author: Vlassara, Helen
ORCID: Zhu, Li
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2006-09-12
Volume: 103
Issue: 37
Pages: 13801-13806
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0600362103
PMC: PMC1564251
OpenAlex: W2092612186
Cited by: 163
References: 40
Citations by year: 2026: 2 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 14 · 2019: 6 · 2018: 3 · 2017: 7 · 2016: 11 · 2015: 10 · 2014: 8 · 2013: 11 · 2012: 9
FWCI: 7.06
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
U.S. Public Health Service (NHL73417)
National Institute on Aging (AG09453, R01AG009453)
National Heart, Lung, and Blood Institute (R01HL073417)
National Institute of Diabetes and Digestive and Kidney Diseases (K08DK065495, DK-65495)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Keywords: advanced glycation end products, EGF receptor, MAPK phosphorylation, NF-κB, oxidative stress, hydrogen peroxide, S100/calgranulins, mesangial cells, diabetes mellitus, aging
MeSH terms: Receptor for Advanced Glycation End Products, Src Homology 2 Domain-Containing, Transforming Protein 1, Animals, Cells, Cultured, Epidermal Growth Factor, Humans, Hydrogen Peroxide, Receptors, Immunologic, Transcriptional Activation, Down-Regulation, Oxidants, Glycation End Products, Advanced, Reactive Oxygen Species, Oxidative Stress, ras Proteins, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Adaptor Proteins, Signal Transducing, Mesangial Cells, Mice, GRB2 Adaptor Protein, Shc Signaling Adaptor Proteins, ErbB Receptors

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Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor

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