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Advanced Glycation End Products (AGEs) and Their Receptor RAGE

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (25 October 2022) | Viewed by 22172

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Prof. Dr. Vincent Sapin

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Guest Editor

Department of Biochemistry and Molecular Genetics, CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France
Interests: receptor of advanced glycation endproducts; retinoids; acute respiratory distress syndrome; premature rupture of membranes; sterile inflammation; diseases biomarkers; traumatic brain injury; S100B protein
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Dr. Loic Blanchon

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Co-Guest Editor

School of Medicine, Université Clermont Auvergne, Clermont-Ferrand, France
Interests: receptor of advanced glycation end products; premature rupture of membranes; fetal membranes; damage associated molecular patterns

Special Issue Information

Dear Colleagues,

Several years ago, the identification and characterization of the advanced glycation end products (AGEs) gave the opportunity to link metabolic disorders (for example, hyperglycaemia) and related pathological disorders in human diseases. The recent discovery of the molecular actor of AGEs, i.e., the trans-membranous receptor of AGE (RAGE) opened up new perspectives in terms of diagnosis and therapeutic aspects of diseases related to AGEs. The complexity of RAGE binding and intracellular activation clearly proposed an interesting explanation of the plurality of the clinical manifestations of such diseases. RAGE belongs to the superfamily of patterns recognition receptors able to link several damage-associated molecular patterns called also alarmins. This molecular link places the pair “AGEs / RAGE” in the global sterile inflammation process developed in a number of acute and chronic human pathologies. This Special Issue, “Advanced Glycation End Products (AGEs) and their receptor RAGE”, aims to provide a summary of the field, to explore recent advances in the biochemical (fundamental and applied) aspects of AGEs, and to discuss what can be developed in terms of biochemistry and pharmacological tools useful for diagnosis and therapeutics in disorders linked with RAGE involvements. We invite authors to submit original research and review articles related to any of these aspects.

Prof. Dr. Vincent Sapin
Dr. Loic Blanchon
Guest Editors

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Keywords

advanced glycation end products
receptor of advanced glycation end products
intracellular transduction pathways
pathophysiology
sterile inflammation
damage-associated molecular patterns

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Published Papers (9 papers)

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Research

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11 pages, 836 KiB

Open AccessCommunication

Availability of Receptors for Advanced Glycation End-Products (RAGE) Influences Differential Transcriptome Expression in Lungs from Mice Exposed to Chronic Secondhand Smoke (SHS)

by Katrina L. Curtis, Ashley Chang, Ryan Van Slooten, Christian Cooper, Madison N. Kirkham, Thomas Armond, Zack deBernardi, Brett E. Pickett, Juan A. Arroyo and Paul R. Reynolds

Int. J. Mol. Sci. 2024, 25(9), 4940; https://doi.org/10.3390/ijms25094940 - 30 Apr 2024

Cited by 1 | Viewed by 1694

Abstract

The receptor for advanced glycation end-products (RAGE) has a central function in orchestrating inflammatory responses in multiple disease states including chronic obstructive pulmonary disease (COPD). RAGE is a transmembrane pattern recognition receptor with particular interest in lung disease due to its naturally abundant pulmonary expression. Our previous research demonstrated an inflammatory role for RAGE following acute exposure to secondhand smoke (SHS). However, chronic inflammatory mechanisms associated with RAGE remain ambiguous. In this study, we assessed transcriptional outcomes in mice exposed to chronic SHS in the context of RAGE expression. RAGE knockout (RKO) and wild-type (WT) mice were delivered nose-only SHS via an exposure system for six months and compared to control mice exposed to room air (RA). We specifically compared WT + RA, WT + SHS, RKO + RA, and RKO + SHS. Analysis of gene expression data from WT + RA vs. WT + SHS showed FEZ1, Slpi, and Msln as significant at the three-month time point; while RKO + SHS vs. WT + SHS identified cytochrome p450 1a1 and Slc26a4 as significant at multiple time points; and the RKO + SHS vs. WT + RA revealed Tmem151A as significant at the three-month time point as well as Gprc5a and Dynlt1b as significant at the three- and six-month time points. Notable gene clusters were functionally analyzed and discovered to be specific to cytoskeletal elements, inflammatory signaling, lipogenesis, and ciliogenesis. We found gene ontologies (GO) demonstrated significant biological pathways differentially impacted by the presence of RAGE. We also observed evidence that the PI3K-Akt and NF-κB signaling pathways were significantly enriched in DEGs across multiple comparisons. These data collectively identify several opportunities to further dissect RAGE signaling in the context of SHS exposure and foreshadow possible therapeutic modalities. Full article

(This article belongs to the Special Issue Advanced Glycation End Products (AGEs) and Their Receptor RAGE)

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14 pages, 2460 KiB

Open AccessArticle

Characterization of RAGE and CK2 Expressions in Human Fetal Membranes

by Karen Coste, Shaam Bruet, Caroline Chollat-Namy, Odile Filhol, Claude Cochet, Denis Gallot, Geoffroy Marceau, Loïc Blanchon, Vincent Sapin and Corinne Belville

Int. J. Mol. Sci. 2023, 24(4), 4074; https://doi.org/10.3390/ijms24044074 - 17 Feb 2023

Viewed by 1591

Abstract

At the feto-maternal interface, fetal membranes (FM) play a crucial role throughout pregnancy. FM rupture at term implicates different sterile inflammation mechanisms including pathways activated by the transmembrane glycoprotein receptor for advanced glycation end-products (RAGE) belonging to the immunoglobulin superfamily. As the protein kinase CK2 is also implicated in the inflammation process, we aimed to characterize the expressions of RAGE and the protein kinase CK2 as a candidate regulator of RAGE expression. The amnion and choriodecidua were collected from FM explants and/or primary amniotic epithelial cells throughout pregnancy and at term in spontaneous labor (TIL) or term without labor (TNL). The mRNA and protein expressions of RAGE and the CK2α, CK2α′, and CK2β subunits were investigated using reverse transcription quantitative polymerase chain reaction and Western blot assays. Their cellular localizations were determined with microscopic analyses, and the CK2 activity level was measured. RAGE and the CK2α, CK2α′, and CK2β subunits were expressed in both FM layers throughout pregnancy. At term, RAGE was overexpressed in the amnion from the TNL samples, whereas the CK2 subunits were expressed at the same level in the different groups (amnion/choriodecidua/amniocytes, TIL/TNL), without modification of the CK2 activity level and immunolocalization. This work paves the way for future experiments regarding the regulation of RAGE expression by CK2 phosphorylation. Full article

(This article belongs to the Special Issue Advanced Glycation End Products (AGEs) and Their Receptor RAGE)

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16 pages, 3576 KiB

Open AccessArticle

A Study on the Protective Effect of sRAGE-MSCs in a Rodent Reperfusion Model of Myocardial Infarction

by Delger Bayarsaikhan, Govigerel Bayarsaikhan, Jaewon Lee and Bonghee Lee

Int. J. Mol. Sci. 2022, 23(24), 15630; https://doi.org/10.3390/ijms232415630 - 9 Dec 2022

Cited by 1 | Viewed by 1723

Abstract

Acute myocardial infarction (AMI) is one of the major leading causes of death in humans globally. Recently, increased levels of recruited macrophages and AGE-albumin were observed in the hearts of humans and animals with acute myocardial infarction. Thus, the purposes of this study were to investigate whether the elevated levels of AGE-albumin from activated macrophage cells are implicated in ischemia-induced cardiomyocyte death and to develop therapeutic strategies for AMI based on its underlying molecular mechanisms with respect to AGEs. The present study demonstrated that activated macrophages and AGE-albumin were observed in heart tissues obtained from humans and rats with AMI incidences. In the cellular model of AMI, it was found that increased expression of AGE-albumin was shown to be co-localized with macrophages, and the presence of AGE-albumin led to increased expression of RAGE through the mitogen-activated protein kinase pathway. After revealing cardiomyocyte apoptosis induced by toxicity of the AGE-RAGE system, sRAGE-secreting MSCs were generated using the CRISPR/Cas9 platform to investigate the therapeutic effects of sRAGE-MSCs in an AMI rat model. Gene-edited sRAGE-MSCs showed greater therapeutic effects against AMI pathogenesis in rat models compared to mock MSCs, and promising results of the functional improvement of stem cells could result in significant improvements in the clinical management of cardiovascular diseases. Full article

(This article belongs to the Special Issue Advanced Glycation End Products (AGEs) and Their Receptor RAGE)

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17 pages, 2417 KiB

Open AccessArticle

Receptor for Advanced Glycation End-Products Promotes Activation of Alveolar Macrophages through the NLRP3 Inflammasome/TXNIP Axis in Acute Lung Injury

by Woodys Lenga Ma Bonda, Marianne Fournet, Ruoyang Zhai, Jean Lutz, Raiko Blondonnet, Céline Bourgne, Charlotte Leclaire, Cécile Saint-Béat, Camille Theilliere, Corinne Belville, Damien Bouvier, Loïc Blanchon, Marc Berger, Vincent Sapin and Matthieu Jabaudon

Int. J. Mol. Sci. 2022, 23(19), 11659; https://doi.org/10.3390/ijms231911659 - 1 Oct 2022

Cited by 8 | Viewed by 2778

Abstract

The roles of thioredoxin-interacting protein (TXNIP) and receptor for advanced glycation end-products (RAGE)-dependent mechanisms of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-driven macrophage activation during acute lung injury are underinvestigated. Cultured THP-1 macrophages were treated with a RAGE agonist (S100A12), with or without a RAGE antagonist; cytokine release and intracytoplasmic production of reactive oxygen species (ROS) were assessed in response to small interfering RNA knockdowns of TXNIP and NLRP3. Lung expressions of TXNIP and NLRP3 and alveolar levels of IL-1β and S100A12 were measured in mice after acid-induced lung injury, with or without administration of RAGE inhibitors. Alveolar macrophages from patients with acute respiratory distress syndrome and from mechanically ventilated controls were analyzed using fluorescence-activated cell sorting. In vitro, RAGE promoted cytokine release and ROS production in macrophages and upregulated NLRP3 and TXNIP mRNA expression in response to S100A12. TXNIP inhibition downregulated NLRP3 gene expression and RAGE-mediated release of IL-1β by macrophages in vitro. In vivo, RAGE, NLRP3 and TXNIP lung expressions were upregulated during experimental acute lung injury, a phenomenon being reversed by RAGE inhibition. The numbers of cells expressing RAGE, NLRP3 and TXNIP among a specific subpopulation of CD16+CD14+CD206- (“pro-inflammatory”) alveolar macrophages were higher in patients with lung injury. This study provides a novel proof-of-concept of complex RAGE–TXNIP–NLRP3 interactions during macrophage activation in acute lung injury. Full article

(This article belongs to the Special Issue Advanced Glycation End Products (AGEs) and Their Receptor RAGE)

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16 pages, 3127 KiB

Open AccessArticle

Effects of RAGE Deletion on the Cardiac Transcriptome during Aging

by Francesco Scavello, Luca Piacentini, Stefania Castiglione, Filippo Zeni, Federica Macrì, Manuel Casaburo, Maria Cristina Vinci, Gualtiero I. Colombo and Angela Raucci

Int. J. Mol. Sci. 2022, 23(19), 11130; https://doi.org/10.3390/ijms231911130 - 22 Sep 2022

Cited by 4 | Viewed by 2186

Abstract

Cardiac aging is characterized by increased cardiomyocyte hypertrophy, myocardial stiffness, and fibrosis, which enhance cardiovascular risk. The receptor for advanced glycation end-products (RAGE) is involved in several age-related diseases. RAGE knockout (Rage−/−) mice show an acceleration of cardiac dimension changes and interstitial fibrosis with aging. This study identifies the age-associated cardiac gene expression signature induced by RAGE deletion. We analyzed the left ventricle transcriptome of 2.5-(Young), 12-(Middle age, MA), and 21-(Old) months-old female Rage−/− and C57BL/6N (WT) mice. By comparing Young, MA, and Old Rage−/− versus age-matched WT mice, we identified 122, 192, and 12 differently expressed genes, respectively. Functional inference analysis showed that RAGE deletion is associated with: (i) down-regulation of genes involved in antigen processing and presentation of exogenous antigen, adaptive immune response, and cellular responses to interferon beta and gamma in Young animals; (ii) up-regulation of genes related to fatty acid oxidation, cardiac structure remodeling and cellular response to hypoxia in MA mice; (iii) up-regulation of few genes belonging to complement activation and triglyceride biosynthetic process in Old animals. Our findings show that the age-dependent cardiac phenotype of Rage−/− mice is associated with alterations of genes related to adaptive immunity and cardiac stress pathways. Full article

(This article belongs to the Special Issue Advanced Glycation End Products (AGEs) and Their Receptor RAGE)

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17 pages, 2117 KiB

Open AccessArticle

Rap1a Activity Elevated the Impact of Endogenous AGEs in Diabetic Collagen to Stimulate Increased Myofibroblast Transition and Oxidative Stress

by Stephanie D. Burr, Christopher C. Dorroh and James A. Stewart, Jr.

Int. J. Mol. Sci. 2022, 23(9), 4480; https://doi.org/10.3390/ijms23094480 - 19 Apr 2022

Cited by 4 | Viewed by 2144

Abstract

Diabetics have an increased risk for heart failure due to cardiac fibroblast functional changes occurring as a result of AGE/RAGE signaling. Advanced glycation end products (AGEs) levels are higher in diabetics and stimulate elevated RAGE (receptor for AGE) signaling. AGE/RAGE signaling can alter the expression of proteins linked to extracellular matrix (ECM) remodeling and oxidative stressors. Our lab has identified a small GTPase, Rap1a, that may overlap the AGE/RAGE signaling pathway. We sought to determine the role Rap1a plays in mediating AGE/RAGE changes and to assess the impact of isolated collagen on further altering these changes. Primary cardiac fibroblasts from non-diabetic and diabetic mice with and without RAGE expression and from mice lacking Rap1a were cultured on tail collagen extracted from non-diabetic or diabetic mice, and in addition, cells were treated with Rap1a activator, EPAC. Protein analyses were performed for changes in RAGE-associated signaling proteins (RAGE, PKC-ζ, ERK1/2) and downstream RAGE signaling outcomes (α-SMA, NF-κB, SOD-2). Increased levels of endogenous AGEs within the diabetic collagen and increased Rap1a activity promoted myofibroblast transition and oxidative stress, suggesting Rap1a activity elevated the impact of AGEs in the diabetic ECM to stimulate myofibroblast transition and oxidative stress. Full article

(This article belongs to the Special Issue Advanced Glycation End Products (AGEs) and Their Receptor RAGE)

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Review

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21 pages, 376 KiB

Open AccessReview

The Potential Influence of Advanced Glycation End Products and (s)RAGE in Rheumatic Diseases

by Charlotte Delrue, Reinhart Speeckaert, Joris R. Delanghe and Marijn M. Speeckaert

Int. J. Mol. Sci. 2023, 24(3), 2894; https://doi.org/10.3390/ijms24032894 - 2 Feb 2023

Cited by 5 | Viewed by 2192

Abstract

Advanced glycation end products (AGEs) are a class of compounds formed by nonenzymatic interactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs can alter the protein structure and activate one of their receptors, specifically the receptor for advanced glycation end products (RAGE). These phenomena impair the functions of cells, extracellular matrix, and tissues. RAGE is expressed by a variety of cells and has been linked to chronic inflammatory autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome. The soluble (s)RAGE cleavage product is a positively charged 48-kDa cleavage product that retains the ligand binding site but loses the transmembrane and signaling domains. By acting as a decoy, this soluble receptor inhibits the pro-inflammatory processes mediated by RAGE and its ligands. In the present review, we will give an overview of the role of AGEs, sRAGE, and RAGE polymorphisms in several rheumatic diseases. AGE overproduction may play a role in the pathogenesis and is linked to accelerated atherosclerosis. Low serum sRAGE concentrations are linked to an increased cardiovascular risk profile and a poor prognosis. Some RAGE polymorphisms may be associated with increased disease susceptibility. Finally, sRAGE levels can be used to track disease progression. Full article

(This article belongs to the Special Issue Advanced Glycation End Products (AGEs) and Their Receptor RAGE)

20 pages, 1378 KiB

Open AccessReview

RAGE against the Machine: Can Increasing Our Understanding of RAGE Help Us to Battle SARS-CoV-2 Infection in Pregnancy?

by Courtney K. Kurashima, Po’okela K. Ng and Claire E. Kendal-Wright

Int. J. Mol. Sci. 2022, 23(12), 6359; https://doi.org/10.3390/ijms23126359 - 7 Jun 2022

Viewed by 2540

Abstract

The receptor of advanced glycation end products (RAGE) is a receptor that is thought to be a key driver of inflammation in pregnancy, SARS-CoV-2, and also in the comorbidities that are known to aggravate these afflictions. In addition to this, vulnerable populations are particularly susceptible to the negative health outcomes when these afflictions are experienced in concert. RAGE binds a number of ligands produced by tissue damage and cellular stress, and its activation triggers the proinflammatory transcription factor Nuclear Factor Kappa B (NF-κB), with the subsequent generation of key proinflammatory cytokines. While this is important for fetal membrane weakening, RAGE is also activated at the end of pregnancy in the uterus, placenta, and cervix. The comorbidities of hypertension, cardiovascular disease, diabetes, and obesity are known to lead to poor pregnancy outcomes, and particularly in populations such as Native Hawaiians and Pacific Islanders. They have also been linked to RAGE activation when individuals are infected with SARS-CoV-2. Therefore, we propose that increasing our understanding of this receptor system will help us to understand how these various afflictions converge, how forms of RAGE could be used as a biomarker, and if its manipulation could be used to develop future therapeutic targets to help those at risk. Full article

(This article belongs to the Special Issue Advanced Glycation End Products (AGEs) and Their Receptor RAGE)

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28 pages, 1470 KiB

Open AccessReview

The Role of Advanced Glycation End Products and Its Soluble Receptor in Kidney Diseases

by Mieke Steenbeke, Reinhart Speeckaert, Stéphanie Desmedt, Griet Glorieux, Joris R. Delanghe and Marijn M. Speeckaert

Int. J. Mol. Sci. 2022, 23(7), 3439; https://doi.org/10.3390/ijms23073439 - 22 Mar 2022

Cited by 36 | Viewed by 3862

Abstract

Patients with chronic kidney disease (CKD) are more prone to oxidative stress and chronic inflammation, which may lead to an increase in the synthesis of advanced glycation end products (AGEs). Because AGEs are mostly removed by healthy kidneys, AGE accumulation is a result of both increased production and decreased kidney clearance. On the other hand, AGEs may potentially hasten decreasing kidney function in CKD patients, and are independently related to all-cause mortality. They are one of the non-traditional risk factors that play a significant role in the underlying processes that lead to excessive cardiovascular disease in CKD patients. When AGEs interact with their cell-bound receptor (RAGE), cell dysfunction is initiated by activating nuclear factor kappa-B (NF-κB), increasing the production and release of inflammatory cytokines. Alterations in the AGE-RAGE system have been related to the development of several chronic kidney diseases. Soluble RAGE (sRAGE) is a decoy receptor that suppresses membrane-bound RAGE activation and AGE-RAGE-related toxicity. sRAGE, and more specifically, the AGE/sRAGE ratio, may be promising tools for predicting the prognosis of kidney diseases. In the present review, we discuss the potential role of AGEs and sRAGE as biomarkers in different kidney pathologies. Full article

(This article belongs to the Special Issue Advanced Glycation End Products (AGEs) and Their Receptor RAGE)

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