Skip to main content

Advertisement

Log in

Understanding RAGE, the receptor for advanced glycation end products

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Advanced glycation end products (AGEs), S100/calgranulins, HMGB1-proteins, amyloid-β peptides, and the family of β-sheet fibrils have been shown to contribute to a number of chronic diseases such as diabetes, amyloidoses, inflammatory conditions, and tumors by promoting cellular dysfunction via binding to cellular surface receptors. The receptor for AGEs (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules acting as counter-receptor for these diverse molecules. Engagement of RAGE converts a brief pulse of cellular activation to sustained cellular dysfunction and tissue destruction. The involvement of RAGE in pathophysiologic processes has been demonstrated in murine models of chronic disease using either a receptor decoy such as soluble RAGE (sRAGE), RAGE neutralizing antibodies, or a dominant-negative form of the receptor. Studies with RAGE−/− mice confirmed that RAGE contributes, at least in part, to the development of late diabetic complications, such as neuropathy and nephropathy, macrovascular disease, and chronic inflammation. Furthermore, deletion of RAGE provided protection from the lethal effects of septic shock caused by cecal ligation and puncture (CLP). In contrast, deletion of RAGE had no effect on the host response in delayed-type hypersensitivity (DTH). Despite the lack of effect seen in adaptive immunity by the deletion of RAGE, administration of the receptor decoy, sRAGE, still afforded a protective effect in RAGE−/− mice. Thus, sRAGE is likely to sequester ligands, thereby preventing their interaction with other receptors in addition to RAGE. These data suggest that, just as RAGE is a multiligand receptor, its ligands are also likely to recognize several receptors in mediating their biologic effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Schmidt AM, Yan SD, Stern DM (1995) The dark side of glucose. Nat Med 1:1002–1004

    Article  PubMed  Google Scholar 

  2. Vlassara H, Bucala R, Striker L (1994) Pathogenetic effects of advanced glycosylation: biochemical, biologic and clinical implications for diabetes and aging. Lab Invest 70:138–151

    PubMed  Google Scholar 

  3. Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP (1998) The AGE/RAGE pathway in vascular disease and diabetes mellitus. Part I: the AGE-concept. Cardiovasc Res 37:586–600

    Article  PubMed  Google Scholar 

  4. Baynes JW (2003) Chemical modification of proteins by lipids in diabetes. Clin Chem Lab Med 41:1159–1165

    Article  PubMed  Google Scholar 

  5. Thornalley PJ (1998) Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs. Cell Mol Biol (Noisy-le-grand) 44:1013–1023

    Google Scholar 

  6. Brownlee M (2000) Negative consequences of glycation. Metabolism 49:9–13

    PubMed  Google Scholar 

  7. Vlassara H, Brownlee M, Cerami A (1985) High affinity receptor mediated uptake and degradation of glucose modified proteins: a potential mechanism for the removal of senescent macromolecules. Proc Natl Acad Sci U S A 82:5588–5592

    PubMed  Google Scholar 

  8. Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pa YCE, Elliston K, Stern DM, Shaw A (1992) Cloning and Expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 267:14998–15004

    PubMed  Google Scholar 

  9. Schmidt AM, Vianna M, Gerlach M, Brett J, Ryan J, Kao Jm Esposito C, Hegarty H, Hurley W, Clauss M, Wang F, Pan YE, Tsang C, Stern D (1992) Isolation and characterisation of two binding proteins gor advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. J Biol Chem 267:14987–14997

    PubMed  Google Scholar 

  10. Schmidt AM, Mora R, Cap R, Yan SD, Brett J, Ramakrishnan R, Tsang TC, Simionescu M, Stern D (1994) The endothelial cell binding site for advanced glycation end products consists of a complex: an integral membrane protein and a lactoferrin-like polypeptide. J Biol Chem 269:9882–9888

    PubMed  Google Scholar 

  11. Lander HM, Taurus JM, Ogiste JS, Hori O, Moss RA, Schmidt AM (1997) Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 272:17810–17814

    Article  PubMed  Google Scholar 

  12. Basta G, Lazzerini G, Massaro M, Simoncini T, Tanganelli P, Fu C, Kislinger T, Stern DM, Schmidt AM, De Caterina R (2002) Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses. Circulation 105:816–822

    Article  PubMed  Google Scholar 

  13. Bucciarelli LG, Wendt T, Rong L, Lalla E, Hofmann MA, Goova MT, Taguchi A, Yan SF, Yan SD, Stern DM, Schmidt AM (2002) RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease.Cell Mol Life Sci 59:1117–1128

    Article  PubMed  Google Scholar 

  14. Schmidt AM, Yan SD, Brett J, Mora R, Nowygrod R, Stern D (1993) Regulation of human mononuclear phagocyte migration by cell surface-binding proteins for advanced glycation end products. J Clin Invest 91:2155–2168

    PubMed  Google Scholar 

  15. Sugaya K, Fukagawa T, Matsumoto K, Mita K, Takahashi E, Ando A, Inoko H, Ikemura T (1994) Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3. Genomics 23:408–419

    Article  PubMed  Google Scholar 

  16. Malherbe R, Richards JG, Gaillard H, Thompson A, Diener C, Schuler A, Huber G (1999) cDNA cloning of a novel secreted isoform of the human receptor for advanced glycation end products and characterisation of cells co-expresing cell-surface scavenger receptors and Swedish mutant amyloid precursor protein. Mol Brain Res 71:159–170

    Article  PubMed  Google Scholar 

  17. Yonekura H, Yamamoto Y, Sakurai S, Petrova RG, Abedin MJ, Li H, Yasui K, Tekuchi M, Makita Z, Takasawa S, Watanabe T, Yamamoto H (2003) Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes and their putative roles in diabetes-induced vascular injury. Biochem J 370:1097–1109

    Article  PubMed  Google Scholar 

  18. Schlueter C, Hauke S, Flohr AM, Rogalla P, Bullerdiek J (2003) Tissue specific expression patterns of the RAGE receptor and its soluble form-a result of regulated alternative splicing? Biochem Biophys Acta 1639:1–6

    PubMed  Google Scholar 

  19. Hanford LE, Enghild JJ, Valnickova Z, Petersen SV, Schaefer LM, Schaefer TM, Reinhart TA, Oury TD (2004) Purification and characterization of mouse soluble Receptor for Advanced Glycation End Products (sRAGE). J Biol Chem 279:50019–50024

    Article  PubMed  Google Scholar 

  20. Schmidt AM, Yan SD, Yan SF, Stern DM (2001) The multiligand receptor RAGE is a progression factor amplifying immune and inflammatory responses. J Clin Invest 108:949–955

    Article  PubMed  Google Scholar 

  21. Du Yan S, Zhu H, Fu J, Yan SF, Roher A, Tourtellotte WW, Rajavashisth T, Chen X, Godman GC, Stern D, Schmidt AM (1997) Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease. Proc Natl Acad Sci U S A 94:5296–5301

    Article  PubMed  Google Scholar 

  22. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691

    Article  PubMed  Google Scholar 

  23. Yan SD, Zhu H, Zhu A, Golabek A, Du H, Roher A, Yu J, Soto C, Schmidt AM, Stern D, Kindy M (2000) Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat Med 6:643–651

    Article  PubMed  Google Scholar 

  24. Hofmann MA, Drury S, Fu C, Wu Q, Taguchi A, Lu Y, Avila C, Kambham N, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Bierhaus A, Neurath M, Nawroth P, Stern D, Schmidt AM (1999) RAGE mediates a novel proinflammatory axis: the cell surface receptor for S100/calgranulin polypeptides. Cell 97:889–901

    Article  PubMed  Google Scholar 

  25. Marenholz I, Heizmann CW, Fritz G (2004) S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem Biophys Res Commun 322:1111–1122

    Article  PubMed  Google Scholar 

  26. Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, Nagashima M, Lundh ER, Vijay S, Nitecki D, Morser J, Stern D, Schmidt AM (1995) The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 270:25752–25761

    Article  PubMed  Google Scholar 

  27. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE., Abumrad NN, Sama A, Tracey KJ (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251

    Article  PubMed  Google Scholar 

  28. Andersson U, Tracey KJ (2003) HMGB1 in sepsis. Scand J Infect Dis 35:577–584

    Article  PubMed  Google Scholar 

  29. Treutiger CJ, Mullins GE, Johansson AS, Rouhiainen A, Rauvala HM, Erlandsson-Harris H, Andersson U, Yang H, Tracey KJ, Andersson J, Palmblad JE (2003) High mobility group 1 B-box mediates activation of human endothelium. J Intern Med 254:375–385

    Article  PubMed  Google Scholar 

  30. Chapman MR, Robinson LS, Pinkner JS, Roth R, Heuser J, Hammar M, Normark S, Hultgren SJ (2002) Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 5556:851–855

    Article  Google Scholar 

  31. Sasaki N, Takeuchi M, Chowei H, Kikuchi S, Hayashi Y, Nakano N, Ikeda H, Yamagishi S, Kitamoto T, Saito T, Makita Z (2002) Advanced glycation end products (AGE) and their receptor (RAGE) in the brain of patients with Creutzfeldt-Jakob disease with prion plaques. Neurosci Lett 326:117–120

    Article  PubMed  Google Scholar 

  32. Chavakis T, Bierhaus A, Schneider D, Linn T, Nagashima K, Arnold B, Preissner KT, Nawroth PP (2003) The pattern recognition receptor (RAGE) is a counter receptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med 198:1507–1515

    Article  PubMed  Google Scholar 

  33. Liliensiek B, Weigand MA, Bierhaus A, Nicklas W, Kasper M, Hofer S, Plaschky J, Gröne HJ, Kurschus FJ, Schmidt AM, Yan SD, Martin E, Schleicher E, Stern DM, Hämmerling GJ, Nawroth PP, Arnold B (2004) Receptor for advanced glycation end products (RAGE) regulates sepsis, but not the adaptive immune response. J Clin Invest 113:1641–1650

    Article  PubMed  Google Scholar 

  34. Gordon S (2002) Pattern recognition receptors: doubling up for the innate immune response. Cell 111:927–930

    Article  PubMed  Google Scholar 

  35. Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 1:675–680

    Article  Google Scholar 

  36. Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert P, Chen J, Hong M, Luther T, Henle T, Klöting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith MA, Perry G, Schmidt AM, Stern DM, Häring HU, Schleicher E, Nawroth PP (2001) Diabetes-associated sustained activation of the transcription factor NF-κB. Diabetes 50:2792–2809

    PubMed  Google Scholar 

  37. Barnes PJ, Karin M (1997) Nuclear factor-κB-a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336:1066–1071

    Article  PubMed  Google Scholar 

  38. Li J, Schmidt AM (1997) Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J Biol Chem 272(1):6498–6506

    Google Scholar 

  39. Bierhaus A, Chen J, Liliensiek B, Nawroth PP (2000) LPS and cytokine activated endothelium. In: Nawroth PP (ed) Seminars in Thrombosis and Hemostasis, vol. 26, pp 571–588

  40. Thompson JE, Phillips RJ, Erdjument-Bromage H, Tempst P, Ghosh S (1995) IκB-β regulates the persistent response in a biphasic activation of NF-κB. Cell 80:573–582

    Article  PubMed  Google Scholar 

  41. Johnson DR, Douglas I, Jahnke A, Ghosh S, Pober JS (1996) A sustained reduction in IκB-β may contribute to persistent NF-κB activation in human endothelial cells. J Biol Chem 271:16317–16322

    Article  PubMed  Google Scholar 

  42. Li JH, Wang W, Huang XR, Oldfield M, Schmidt AM, Cooper ME, Lan HY (2004) Advanced glycation end products induce tubular epithelial-myofibroblast transition through the RAGE-ERK1/2 MAP kinase signaling pathway. Am J Pathol 164:1389–1397

    PubMed  Google Scholar 

  43. Sorci G, Riuzzi F, Agneletti AL, Marchetti C, Donato R (2004) S100B causes apoptosis in a myoblast cell line in a RAGE-independent manner. J Cell Physiol 199:274–283

    Article  PubMed  Google Scholar 

  44. Cortizo AM, Lettieri MG, Barrio DA, Mercer N, Etcheverry SB, McCarthy AD (2003) Advanced glycation end-products (AGEs) induce concerted changes in the osteoblastic expression of their receptor RAGE and in the activation of extracellular signal-regulated kinases (ERK). Mol Cell Biochem 250:1–10

    Article  PubMed  Google Scholar 

  45. Shanmugam N, Kim YS, Lanting L, Natarajan R (2003) Regulation of cyclooxygenase-2 expression in monocytes by ligation of the receptor for advanced glycation end products. J Biol Chem 278:34834–34844

    Article  PubMed  Google Scholar 

  46. Ishihara K, Tsutsumi K, Kawane S, Nakajima M, Kasaoka T (2003) The receptor for advanced glycation end-products (RAGE) directly binds to ERK by a D-domain-like docking site. FEBS Lett 550:107–113

    Article  PubMed  Google Scholar 

  47. Yeh CH, Sturgis L, Haidacher J, Zhang XN, Sherwood SJ, Bjercke RJ, Juhasz O, Crow MT, Tilton RG, Denner L (2001) Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. Diabetes 50:1495–1504

    PubMed  Google Scholar 

  48. Sorci G, Riuzzi F, Arcuri C, Giambanco I, Donato R (2004) Amphoterin stimulates myogenesis and counteracts the antimyogenic factors basic fibroblast growth factor and S100B via RAGE binding. Mol Cell Biol 24:4880–4894

    Article  PubMed  Google Scholar 

  49. Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa S, Stern DM, Schmidt AM (2000) Blockade of RAGE-amphoterin signaling suppresses tumour growth and metastases. Nature 405:354–360

    Article  PubMed  Google Scholar 

  50. Huttunen HJ, Fages C, Rauvala H (1999) Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem 274:19919–19924

    Article  PubMed  Google Scholar 

  51. Huang JS, Guh JY, Chen HC, Hung WC, Lai YH, Chuang LY (2001) Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. J Cell Biochem 81:102–113

    Article  PubMed  Google Scholar 

  52. Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL (2001) Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 280:E685–E694

    PubMed  Google Scholar 

  53. Bierhaus A, Chevion S, Chevion M, Hofmann M, Quehenberger P, Illmer T, Luther T, Wahl P, Tritschler H, Müller M, Ziegler R, Nawroth PP (1997) Advanced glycation endproduct (AGEs) induced activation of NF-κB is suppressed by α-lipoic acid in cultured endothelial cells. Diabetes 46:1481–1490

    Google Scholar 

  54. Thornalley PJ (1998) Glutathione-dependent detoxification of alpha-oxoaldehydes by the glyoxalase system: involvement in disease mechanisms and antiproliferative activity of glyoxalase I inhibitors. Chem Biol Interact 111:137–151

    Article  PubMed  Google Scholar 

  55. Degenhard TP, Thorpe SR, Baynes J (1988) Chemical modification of proteins by methylglyoxal. Cell Mol Biol (Noisy-le-grand) 44:1139–1145

    Google Scholar 

  56. Thornalley PJ, Langborg A, Minhas HS (1999) Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem J 344(Pt 1):109–116

    Article  Google Scholar 

  57. Shinohara M, Thornalley PJ, Giardino I, Beisswenger P, Thorpe SR, Onorato J, Brownlee M (1998) Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecule endocytosis. J Clin Invest 101:1142–1147

    PubMed  Google Scholar 

  58. Morcos M, Sayed A, Pfisterer F, Hutter H, Thornalley P, Ahmed N, Miftari N, Mörlen F, Hamann A, Bierhaus A, Nawroth PP (2004) Glyoxalase I als endogener Schutz vor Advanced Glycation Endproducts (AGE)-formation und oxidativem stress in Caenorhabditis elegans. Diab Stoffw 13(Supplementheft 1):33 V-70

    Google Scholar 

  59. Brett J, Schmidt AM, Yan SD, Zhou YS, Weidmann E, Pinsky D, Nowygrod R, Neeper M, Przysiecki C, Dhaw A, Migheli A, Stern DM (1993) Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissue. Am J Pathol 143:1699–1712

    PubMed  Google Scholar 

  60. Kokkola R, Andersson A, Mullins G, Ostberg T, Treutiger CJ, Arnold B, Nawroth P, Andersson U, Harris RA, Harris HE (2005) RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages. Scand J Immunol 61:1–9

    Article  PubMed  Google Scholar 

  61. Anderson MM, Requena JR, Crowley JR, Thorpe SR, Heinecke JW (1999) The myeloperoxidase system of human phagocytes generates Nepsilon-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycated endproduts at sites of inflammation. J Clin Invest 104:103–113

    PubMed  Google Scholar 

  62. Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern D, Schmidt AM (1999) N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem 274:31740–31749

    Article  PubMed  Google Scholar 

  63. Brownlee M (2000) Negative consequences of glycation. Metabolism 49:9–13

    PubMed  Google Scholar 

  64. Schiekofer S, Andrassy M, Schneider J, Fritsche A, Chen J, Humpert P, Stumvoll M, Schleicher E, Häring HU, Nawroth PP, Bierhaus A (2003) Acute (2 h) hyperglycemic clamp causes intracellular formation of carboxymethyllysine, activation of Ras, p42/p44 MAPK and NF-κB in peripheral blood mononuclear cells. Diabetes 52:621–633

    PubMed  Google Scholar 

  65. Mackic JB, Stins M, McComb JG, Calero M, Ghiso J, Kim KS, Yan SD, Stern D, Schmidt AM, Frangione B, Zlokovic BV (1998) Human blood-brain barrier receptors for Alzheimer’s amyloid-beta 1–40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. J Clin Invest 102:734–743

    PubMed  Google Scholar 

  66. Abel M, Ritthaler U, Zhang Y, Deng Y, Schmidt AM, Greten J, Sernau T, Wahl P, Andrassy K, Ritz R, Waldherr R, Stern DM, Nawroth PP (1995) Expression of receptors for advanced glycosylated end products in renal disease. Nephrol Dial Transplant 10:1662–1667

    PubMed  Google Scholar 

  67. Ritthaler U, Deng Y, Zhang Y, Greten J, Abel M, Sido B, Allenberg J, Otto G, Roth H, Bierhaus A, Ziegler R, Schmidt AM, Waldherr R, Wahl P, Stern DM, Nawroth PP (1995) Expression of receptors for advanced glycation end products in peripheral occlusive vascular disease. Am J Pathol 146:688–694

    PubMed  Google Scholar 

  68. Lalla E, Lamster IB, Stern DM, Schmidt AM (2001) Receptor for advanced glycation end products, inflammation, and accelerated periodontal disease in diabetes: mechanisms and insights into therapeutic modalities. Ann Periodontol 6:113–118

    Article  PubMed  Google Scholar 

  69. Wendt TM, Tanji N, Kislinger TR, Qu W, Lu Y, Bucciarelli LG, Rong L, Bierhaus A, Nawroth PP, Moser B, Markowitz GS, Stein G, Dágati V, Stern DM, Schmidt AM (2003) RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 162:1123–1137

    PubMed  Google Scholar 

  70. Bierhaus A, Haslbeck KM, Humpert PM, Liliensiek B, Dehmer T, Morcos M, Sayed AA, Andrassy M, Schiekofer S, Schneider J, Schulz J, Heuss D, Neundörfer B, Dierl S, Huber J, Tritschler H, Schmidt AM, Schwaninger M, Häring HU, Schleicher E, Stern DM, Kasper M, Arnold B, Nawroth PP (2004) Loss of pain perception in diabetic neuropathy is dependent on a receptor of the immune globulin superfamily. J Clin Invest 114:1741–1751

    Article  PubMed  Google Scholar 

  71. Sakaguchi T, Yan SF, Yan SD, Belov D, Rong LL, Sousa M, Andrassy M, Marso SP, Duda S, Arnold B, Liliensiek B, Nawroth PP, Stern DM, Schmidt AM, Naka Y (2003) Central role of RAGE-dependent neointimal expansion in arterial restenosis. J Clin Invest 111:959–972

    Article  PubMed  Google Scholar 

  72. Kislinger T, Tanji N, Wendt T, Qu W, Lu Y, Ferran LJ Jr, Taguchi A, Olson K, Bucciarelli L, Goova M, Hofmann MA, Cataldegirmen G, D’Agati V, Pischetsrieder M, Stern DM, Schmidt AM (2001) Receptor for advanced glycation end products mediates inflammation and enhanced expression of tissue factor in vasculature of diabetic apolipoprotein E-Null mice. Arterioscl Thromb Vasc Biol 21:905–910

    PubMed  Google Scholar 

  73. Park L, Raman KG, Lee KJ, Lu Y, Ferran LJ Jr, Chow WS, Stern DM, Schmidt AM (1998) Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med 4:1025–1031

    Article  PubMed  Google Scholar 

  74. Drinda S, Franke S, Ruster M, Petrow P, Pullig O, Stein G, Hein G (2004) Identification of the receptor for advanced glycation end products in synovial tissue of patients with rheumatoid arthritis. Rheumatol Int [Epub ahead of print]

  75. Chen Y, Yan SS, Colgan J, Zhang HP, Luban J, Schmidt AM, Stern D, Herold KC (2004) Blockade of late stages of autoimmune diabetes by inhibition of the receptor for advanced glycation end products. J Immunol 173:1399–1405

    PubMed  Google Scholar 

  76. Goosa MT, Li J, Kislinger T, Qu W, Lu Y, Bucciarelli LG, Nowgrod S, Wolf BM, Calistle X, Yan SD, Stern DM, Schmidt AM (2001) Blockade of receptor for Advanced Glycation Endproducts restores effective wound healing in diabetic mice. Am J Pathol 159:513–525

    PubMed  Google Scholar 

  77. Hudson BI, Bucciarelli LG, Wendt T et al (2003) Blockade of receptor for advanced glycation endproducs: a new target for therapeutic intervention in diabetic complications and inflammatory disorders. Arch Biochem Biophys 419:80–88

    Article  PubMed  Google Scholar 

  78. Lue LF, Walker DG, Brachova L, Beach TG, Rogers J, Schmidt AM, Stern DM, Yan SD (2001) Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer’s disease: identification of a cellular activation mechanism. Exp Neurol 171:29–45

    Article  PubMed  Google Scholar 

  79. Arancio O, Zhang HP, Chen X, Lin C, Trinchese F, Puzzo D, Liu S, Hegde A, Yan SF, Stern A, Luddy JS, Lue LF, Walker DG, Roher A, Buttini M, Mucke L, Li W, Schmidt AM, Kindy M, Hyslop PA, Stern DM, Du Yan SS (2004) RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J 23:4096–4105

    Article  PubMed  Google Scholar 

  80. Constien R, Forde A, Liliensiek B, Grone HJ, Nawroth PP, Hammerling G, Arnold B (2001) Characterization of a novel EGFP reporter mouse to monitor Cre recombination as demonstrated by a Tie2 Cre mouse line. Genesis 30:36–44

    Article  PubMed  Google Scholar 

  81. Robinson MJ, Tessier P, Poulsom R, Hogg N (2002) The S100 family heterodimer, MRP-8/14, binds with high affinity to heparin and heparan sulfate glycosaminoglycans on endothelial cells. J Biol Chem 277:3658–3665

    Article  PubMed  Google Scholar 

  82. Erlandsson Harris H, Andersson U (2004) Mini-review: the nuclear protein HMGB1 as a proinflammatory mediator. Eur J Immunol 34:1503–1512

    Article  PubMed  Google Scholar 

  83. Yamamoto Y, Kazio I, Doi T et al (2001) Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. J Clin Invest 108:261–268

    Article  PubMed  Google Scholar 

  84. Yajima N, Yamamoto Y, Yamamoto H, Takeuchi M, Yaghihashi S (2004) Peripheral neuropathy in diabetic mice overexpressing receptor for advanced glycation endproducts (RAGE). Collected abstracts of the 8th International Symposium on the Maillard reaction (Charleston, SC): no. SXI-7; 55

  85. Baeuerle PA, Henkel T (1994) Function and activation of NF-κB in the immune system. Annu Rev Immun 12:141–179

    PubMed  Google Scholar 

  86. Yan SS, Wu ZY, Zhang HP, Furtado G, Chen X, Yan SF, Schmidt AM, Brown C, Stern A, Lafaille J, Chess L, Stern DM, Jiang H (2003) Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system. Nat Med 9:287–293

    Article  PubMed  Google Scholar 

  87. Gold JA, Parsey M, Hoshino Y, Hoshino S, Nolan A, Yee T, Tse DB, Weiden MD (2003) CD40 contributes to lethality in acute sepsis: in vivo role for CD40 in innate immunity. Infect Immun 71:3521–3528

    Article  PubMed  Google Scholar 

  88. Chavakis T, Bierhaus A, Nawroth PP (2004) RAGE-a central player in the inflammatory

  89. Fages C, Nolo R, Huttunen HJ, Eskelinen E, Rauvala H (2000) Regulation of cell migration by amphoterin. J Cell Sci 113:611–620

    PubMed  Google Scholar 

  90. Huttunen HJ, Kuja-Panula J, Sorci G, Agneletti AL, Donato R, Rauvala H (2000) Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation. J Biol Chem 275:40096–40105

    Article  PubMed  Google Scholar 

  91. Rong LL, Trojaborg W, Qu W, Kostov K, Yan SD, Gooch C, Szabolcs M, Hays AP, Schmidt AM (2004) Antagonism of RAGE suppresses peripheral nerve regeneration. FASEB J 18:1812–1817

    Article  PubMed  Google Scholar 

  92. Rong LL, Yan SF, Wendt T, Hans D, Pachydaki S, Bucciarelli LG, Adebayo A, Qu W, Lu Y, Kostov K, Lalla E, Yan SD, Gooch C, Szabolcs M, Trojaborg W, Hays AP, Schmidt AM (2004) RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways. FASEB J 18:1818–1825

    Article  PubMed  Google Scholar 

  93. Bartling B, Hofmann HS, Weigle B, Silber RE, Simm A (2004) Down-regulation of the receptor for advanced glycation endproducts (RAGE) supports non-small cell lung carcinoma. Carcinogenesis [Epub ahead of print]

  94. Huttunen HJ, Fages C, Kuja-Panula J, Ridley AJ, Rauvala H (2002) Receptor for advanced glycation end products-binding COOH-terminal motif of amphoterin inhibits invasive migration and metastasis. Cancer Res 62:4805–4811

    PubMed  Google Scholar 

  95. Vlassara H, Palace MR (2002) Diabetes and advanced glycation endproducts. J Intern Med 251:87–101

    Article  PubMed  Google Scholar 

  96. He CJ, Zheng F, Stitt A, Striker L, Hattori M, Vlassara H (2000) Differential expression of renal AGE-receptor genes in NOD mice: possible role in nonobese diabetic renal disease. Kidney Int 58:1931–1940

    Article  PubMed  Google Scholar 

  97. Stitt AW, He C, Vlassara H (1999) Characterization of the advanced glycation end-product receptor complex in human vascular endothelial cells. Biochem Biophys Res Commun 256:549–556

    Article  PubMed  Google Scholar 

  98. Pugliese G, Pricci F, Iacobini C, Leto G, Amadio L, Barsotti P, Frigeri L, Hsu DK, Vlassara H, Liu FT, Di Mario U (2001) Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice. FASEB J 15:2471–2479

    Article  PubMed  Google Scholar 

  99. Ohgami N, Naga R, Ikemoto M, Arai H, Miyazaki A, Hakamata H, Horiuchi S, Nakayama H (2002) CD36, serves as a receptor for advanced glycation endproducts (AGE). J Diabetes its Complicat 16:56–59

    Article  Google Scholar 

  100. Srikrishna G, Huttunen HJ, Johansson L, Weigle B, Yamaguchi Y, Rauvala H, Freeze HH (2002) N-Glycans on the receptor for advanced glycation end products influence amphoterin binding and neurite outgrowth. J Neurochem 80:998–1008

    Article  PubMed  Google Scholar 

  101. McRobert EA, Gallicchio M, Jerums G, Cooper ME, Bach LA (2003) The amino-terminal domains of the ezrin, radixin, and moesin (ERM) proteins bind advanced glycation end products, an interaction that may play a role in the development of diabetic complications. J Biol Chem 278:25783–25789

    Article  PubMed  Google Scholar 

  102. Saito A, Nagai R, Tanuma A, Hama H, Cho K, Takeda T, Yoshida Y, Toda T, Shimizu F, Horiuchi S, Gejyo F (2003) Role of megalin in endocytosis of advanced glycation end products: implications for a novel protein binding to both megalin and advanced glycation end products. J Am Soc Nephrol 14:1123–1131

    Article  PubMed  Google Scholar 

  103. Lu C, He JC, Cai W, Liu H, Zhu L, Vlassara H (2004) Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells. Proc Natl Acad Sci U S A 101:11767–11772

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was in part supported by grants from the Deutsche Forschungsgemeinschaft (SFB 405 to PPN), the European Foundation for the Study of Diabetes (AB), the German Diabetes Association (AB; PMH), and the Juvenile Diabetes Research Foundation (AB; PPN).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Angelika Bierhaus.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bierhaus, A., Humpert, P.M., Morcos, M. et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med 83, 876–886 (2005). https://doi.org/10.1007/s00109-005-0688-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-005-0688-7

Keywords

Navigation