The Receptor for Advanced Glycation End Products (RAGE) Specifically Recognizes Methylglyoxal-Derived AGEs

Xue, Jing; Ray, Rashmi; Singer, David; Böhme, David; Burz, David S.; Rai, Vivek; Hoffmann, Ralf; Shekhtman, Alexander

doi:10.1021/bi500046t

Cited by 148 publications

(130 citation statements)

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“…14,15 Receptor for advanced glycation end products (RAGE) has also been identified as a binding partner for SAA. 7,12,[16][17][18] RAGE is a cell surface receptor of the immunoglobulin superfamily involved in important processes, such as cell migration, adhesion, and proliferation 19-22 RAGE was first described as a binding partner for AGEs 23,24 ; however, proteins from the S100 family, amyloid fibrils, high mobility group box 1, C3a, and CpG DNA oligonucleotides can trigger a proinflammatory response via RAGE.20 RAGE signaling is, therefore, involved in the pathogenesis of several diseases, including diabetes mellitus, cancer, autoimmune disorders, neurodegenerative and vascular diseases. 17,18,20,22,25,26 RAGE signaling has been implicated in uremia-induced atherosclerosis.…”

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confidence: 99%

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confidence: 99%

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Signaling of Serum Amyloid A Through Receptor for Advanced Glycation End Products as a Possible Mechanism for Uremia-Related Atherosclerosis

Belmokhtar

Robert

Ortillon

et al. 2016

ATVB

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Objective-Cardiovascular disease is the leading cause of death in patients with end-stage renal disease. Serum amyloid A (SAA) is an acute phase protein and a binding partner for the multiligand receptor for advanced glycation end products (RAGE). We investigated the role of the interaction between SAA and RAGE in uremia-related atherogenesis. Approach and Results-We used a mouse model of uremic vasculopathy, induced by 5 of 6 nephrectomy in the Apoe −/− background. Sham-operated mice were used as controls. Primary cultures of Ager +/+ and Ager −/− vascular smooth muscle cells (VSMCs) were stimulated with recombinant SAA, S100B, or vehicle alone. Relevance to human disease was assessed with human VSMCs. The surface area of atherosclerotic lesions at the aortic roots was larger in uremic Apoe −/− than in sham-operated Apoe −/− mice (P<0.001). Furthermore, atherosclerotic lesions displayed intense immunostaining for RAGE and SAA, with a pattern similar to that of α-SMA. Ager transcript levels in the aorta were 6× higher in uremic animals than in controls (P<0.0001). Serum SAA concentrations were higher in uremic mice, not only after 4 weeks of uremia but also at 8 and 12 weeks of uremia, than in sham-operated animals. We investigated the functional role of RAGE in uremia-induced atherosclerosis further, in animals lacking RAGE. We found that the induction of uremia in Apoe −/− Ager −/− mice did not accelerate atherosclerosis. In vitro, the stimulation of Ager +/+ but not of Ager −/− VSMCs with SAA or S100B significantly induced the production of reactive oxygen species, the phosphorylation of AKT and mitogenactivated protein kinase-extracellular signal-regulated kinases and cell migration. Reactive oxygen species inhibition with N-acetyl cysteine significantly inhibited both the phosphorylation of AKT and the migration of VSMCs. Similar results were obtained for human VSMCs, except that the phosphorylation of mitogen-activated protein kinase-extracellular signal-regulated kinases, rather than of AKT, was subject to specific redox-regulation by SAA and S100B. Furthermore, human aortic atherosclerotic sections were positively stained for RAGE and SAA. Conclusions-Uremia upregulates SAA and RAGE expression in the aortic wall and in atherosclerotic lesions in mice. Ager −/− animals are protected against the uremia-induced acceleration of atherosclerosis. SAA modulates the functions of murine and human VSMCs in vitro in a RAGE-dependent manner. This study, therefore, identifies SAA as a potential new uremic toxin involved in uremia-related atherosclerosis through interaction with RAGE. This manuscript was sent to Ryozo Nagai, Consulting Editor, for review by expert referees, editorial decision, and final disposition. marker of cardiovascular risk. 6 High levels have been reported in uremic patients and are independently associated with cardiovascular mortality.7 SAA has also been reported to play an active role in the atherogenic process. 6,8,9 First, SAA has been detected in the atherosclerotic lesions of hyperlipidem...

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confidence: 99%

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confidence: 99%

Signaling of Serum Amyloid A Through Receptor for Advanced Glycation End Products as a Possible Mechanism for Uremia-Related Atherosclerosis

Belmokhtar

Robert

Ortillon

et al. 2016

ATVB

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“…AGEs were also shown to inhibit cell growth and increase apoptosis in ST2 cells (40). CML and MG-H1 are well-known ligands for RAGE, and their interactions may lead to diabetic complications (41). Therefore, MGO in itself, and its derivatives, such as AGE, all account for detrimental bone healing in diabetes.…”

Section: Discussionmentioning

confidence: 99%

Contribution of methylglyoxal to delayed healing of bone injury in diabetes

Aikawa

Matsubara

Ugaji

et al. 2017

Molecular Medicine Reports

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Abstract.Patients with diabetes are vulnerable to delayed bone fracture healing or pseudoarthrosis. Chronic sustained hyperglycemia, reactive intermediate derivatives of glucose metabolism, such as methylglyoxal (MGO), and advanced glycation end-products (AGEs) are implicated in diabetic complications. In the present study, it was examined whether MGO is able to cause disturbed bone healing in diabetes. Diabetes was induced in male mice by injection of streptozotocin (50 mg/kg) for 5 days. A bone defect (1.0-mm diameter) was created in the left distal femur, and bone repair was assessed from an examination of computed tomography scans. ST2 cells were exposed to MGO (0-400 µM) to investigate osteoblastic differentiation, cell viability, and damage. Consequently, blood glucose and hemoglobin A1c levels in diabetic mice were determined to be 493±14.1 mg/dl and 8.0±0.05%, respectively. Compared with non-diabetic control mice, diabetic mice exhibited markedly delayed bone healing, with increased levels of the MGO-derived AGEs, N ε -(carboxymethyl)-lysine and N δ -(5-hydro-5-methyl-4-imida zolone-2-yl)-ornithine, in the sera and femurs. MGO inhibited the osteoblastic differentiation of ST2 cells in a dose-dependent manner, and markedly decreased cell proliferation through cytotoxicity. In conclusion, MGO has been demonstrated to cause impaired osteoblastic differentiation and delayed bone repair in diabetes. Therefore, detoxification of MGO may be a potentially useful strategy against bone problems in patients with diabetes.

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“…Post-translationally glycated proteins are thought to exert their effects on cells by a receptor-mediated pathway that includes their interaction with a receptor recognizing AGE-modified proteins. The receptor, termed RAGE, is a member of the immunoglobulin superfamily of cell-surface receptors and specifically recognizes MG-modified AGEs (120). This interaction appears to result in cellular activation leading ultimately to inflammation-provoking tissue injury (13).…”

Section: Advanced Glycation End-products (Age) and The Dicarbonyl Promentioning

confidence: 99%

Glyoxalase biochemistry

Honek

2015

Biomolecular Concepts

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Abstract:The glyoxalase enzyme system utilizes intracellular thiols such as glutathione to convert α-ketoaldehydes, such as methylglyoxal, into D-hydroxyacids. This overview discusses several main aspects of the glyoxalase system and its likely function in the cell. The control of methylglyoxal levels in the cell is an important biochemical imperative and high levels have been associated with major medical symptoms that relate to this metabolite's capability to covalently modify proteins, lipids and nucleic acid.

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The Receptor for Advanced Glycation End Products (RAGE) Specifically Recognizes Methylglyoxal-Derived AGEs

Cited by 148 publications

References 49 publications

Signaling of Serum Amyloid A Through Receptor for Advanced Glycation End Products as a Possible Mechanism for Uremia-Related Atherosclerosis

Signaling of Serum Amyloid A Through Receptor for Advanced Glycation End Products as a Possible Mechanism for Uremia-Related Atherosclerosis

Contribution of methylglyoxal to delayed healing of bone injury in diabetes

Glyoxalase biochemistry

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