Inhibition of RAGE Axis Signaling: A Pharmacological Challenge

Author(s): Armando Rojas*, Miguel Morales, Ileana Gonzalez, Paulina Araya

Journal Name: Current Drug Targets

Volume 20 , Issue 3 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


The Receptor for Advanced Glycation End Products (RAGE) is an important cell surface receptor, which belongs to the IgG super family and is now considered as a pattern recognition receptor. Because of its relevance in many human clinical settings, it is now pursued as a very attractive therapeutic target. However, particular features of this receptor such as a wide repertoire of ligands with different binding domains, the existence of many RAGE variants as well as the presence of cytoplasmatic adaptors leading a diverse signaling, are important limitations in the search for successful pharmacological approaches to inhibit RAGE signaling. Therefore, the present review aimed to display the most promising approaches to inhibit RAGE signaling, and provide an up to date review of progress in this area.

Keywords: Receptor of advanced glycation end-products, advanced glycation end-products, intracellular signaling, antagonists, inhibitors, cytoplasmatic adaptors.

Rojas A, González I, Añazco C. In: Dietary AGEs and their roles in health and disease; Jaime Uribarri. CRC Press 2017; pp. 37-49.
Brownlee M. Advanced protein glycosylation in diabetes and aging. Annu Rev Med 1995; 46: 223-34.
Rojas A, Morales MA. Advanced glycation and endothelial functions: A link towards vascular complications in diabetes. Life Sci 2004; 76(7): 715-30.
Vistoli G, De Maddis D, Cipak A, et al. Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): An overview of their mechanisms of formation. Free Radic Res 2013; 471. : 3-27.
Henning C, Glomb MA. Pathways of the Maillard reaction under physiological conditions. Glycoconj J 2016; 33(4): 499-512.
Senatus L, Schmidt AM. The AGE-RAGE Axis: Implications for Age-associated arterial diseases. Front Genet 2017; 8: 187.
Yamagishi SI, Nakamura N, Matsui T. Glycation and cardiovascular disease in diabetes: A perspective on the concept of metabolic memory. J Diabetes 2017; 9(2): 141-8.
Frimat M, Daroux M, Litke R, et al. Kidney, heart and brain: three organs targeted by ageing and glycation. Clin Sci (Lond) 2017; 131(11): 1069-92.
Khan MI, Rath S, Adhami VM, et al. H. Hypoxia driven glycation: Mechanisms and therapeutic opportunities. Semin Cancer Biol 2018; 49(April): 75-8.
Rojas A, Perez R, González I, et al. The emerging role of the receptor for advanced glycation end products on innate immunity. Int Rev Immunol 2014; 33(1): 67-80.
Rojas A, Delgado F, González I, et al. The receptor for advanced glycation end-products: a complex signaling scenario for a promiscuous receptor. Cell Signal 2013; 25(3): 609-14.
Shekhtman A, Ramasamy R, Schmidt AM. Glycation & the RAGE axis: targeting signal transduction through DIAPH1. Expert Rev Proteomics 2017; 14(2): 147-56.
Ott C, Jacobs K, Haucke E, et al. Role of advanced glycation end products in cellular signaling. Redox Biol 2014; 2: 411-29.
Lazzari P, Pau A, Tambaro S, et al. Synthesis and pharmacological evaluation of novel 4-alkyl-5-thien-2′-yl pyrazole carboxamides. Cent Nerv Syst Agents Med Chem 2012; 12(4): 254-76.
Lazzari P, Serra V, Marcello S, et al. A. Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats. Eur Neuropsychopharmacol 2017; 27(7): 667-78.
Tambaro S, Casu MA, Mastinu A, et al. Evaluation of selective cannabinoid CB(1) and CB(2) receptor agonists in a mouse model of lipopolysaccharide-induced interstitial cystitis. Eur J Pharmacol 2014; 729: 67-74.
Schmidt AM. 2016 ATVB Plenary Lecture: Receptor for Advanced Glycation Endproducts and implications for the pathogenesis and treatment of cardiometabolic disorders: Spotlight on the macrophage. Arterioscler Thromb Vasc Biol 2017; 37(4): 613-21.
Cohen MM. Perspectives on RAGE signaling and its role in cardiovascular disease. Am J Med Genet A 2013; 161A(11): 2750-5.
Chuah YK, Basir R, Talib H, et al. Receptor for advanced glycation end- products and its involvement in inflammatory diseases. Int J Inflamm 2013; 2013: 40346.
Fukami K, Taguchi K, Yamagishi S, et al. Receptor for advanced glycation endproducts and progressive kidney disease. Curr Opin Nephrol Hypertens 2015; 24(1): 54-60.
Ray R, Juranek JK, Rai V. RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis. Neurosci Biobehav Rev 2016; 62: 48-55.
Nienhuis HL, Westra J, Smit AJ, et al. AGE and their receptor RAGE in systemic autoimmune diseases: An inflammation propagating factor contributing to accelerated atherosclerosis. Autoimmunity 2009; 42(4): 302-4.
Vlassara H, Striker GE. Advanced glycation end-products in diabetes and diabetic complications. Endocrinol Metab Clin North Am 2013; 42(4): 697-719.
Santos J, Valentim C, de Araujo IB, et al. Development of nonalcoholic hepatopathy: contributions of oxidative stress and advanced glycation end products. Int J Mol Sci 2013; 14: 19846-66.
Juranek J, Ray R, Banach M, Rai V. Receptor for advanced glycation end-products in neurodegenerative diseases. Rev Neurosci 2015; 26(6): 691-8.
Malik P, Chaudhry N, Narender M, et al. Role of receptor for advanced glycation end products in the complication and progression of various types of cancers. Biochim Biophys Acta 2015; 1850(9): 1898-904.
Nienhuis HL, Westra J, Smit AJ, et al. AGE and their receptor RAGE in systemic autoimmune diseases: An inflammation propagating factor contributing to accelerated atherosclerosis. Autoimmunity 2009; 42(4): 302-4.
Rojas A, Añazco C, González I, et al. Extracellular matrix glycation and receptor for advanced glycation end-products activation: a missing piece in the puzzle of the association between diabetes and cancer. Carcinogenesis 2018; 39(4): 515-21.
Rojas A, González I, Morales E, et al. Diabetes and cancer: Looking at the multiligand/RAGE axis. World J Diabetes 2011; 2(7): 108-13.
Huber R, Meier B, Otsuka A, et al. Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages. Sci Rep 2016; 6: 29914.
Rojas A, Delgado-López F, Perez-Castro R, et al. HMGB1 enhances the protumoral activities of M2 macrophages by a RAGE-dependent mechanism. Tumour Biol 2016; 37(3): 3321-9.
Rojas A, Araya P, Romero J, et al. HMGB1-mediated RAGE activation mechanism in M2 macrophages. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research, New Orleans, USA; April 16-20, 2016. Cancer Res 2016; 76(14): 725.
Ramasamy R, Yan SF, Schmidt AM. RAGE: therapeutic target and biomarker of the inflammatory response--the evidence mounts. J Leukoc Biol 2009; 86(3): 505-12.
Hudson BI, Carter AM, Harja E, et al. Identification, classification, and expression of RAGE gene splice variants. FASEB J 2008; 22(5): 1572-80.
Yatime L, Andersen GR. Structural insights into the oligomerization mode of the human receptor for advanced glycation end-products. FEBS J 2013; 280(24): 6556-68.
Kalea AZ, Schmidt AM, Hudson BI. Alternative splicing of RAGE: roles in biology and disease. Front Biosci (Landmark Ed) 2011; 16: 2756-70.
Yan SF, Ramasamy R, Schmidt AM. The receptor for advanced glycation endproducts (RAGE) and cardiovascular disease. Expert Rev Mol Med 2009; 11e9.
Jules J, Maiguel D, Hudson BI. Alternative splicing of the RAGE cytoplasmic domain regulates cell signaling and function. PLoS One 2013; 8(11): e78267.
Logsdon CD, Fuentes MK, Huang EH, et al. RAGE and RAGE ligands in cancer. Curr Mol Med 2007; 7(8): 777-89.
Yamagishi S, Matsui T, Fukami K. Role of receptor for advanced glycation end products (RAGE) and its ligands in cancer risk. Rejuvenation Res 2015; 18(1): 48-5.
Song J, Lee WT, Park KA, Lee JE. Receptor for advanced glycation end products (RAGE) and its ligands: Focus on spinal cord injury. Int J Mol Sci 2014; 15(8): 13172-91.
Mizumoto S, Sugahara K. Glycosaminoglycans are functional ligands for receptor for advanced glycation end-products in tumors. FEBS J 2013; 280(10): 2462-70.
Rouhiainen A, Kuja-Panula J, Tumova S, et al. RAGE-mediated cell signaling. Methods Mol Biol 2013; 963: 239-63.
González I, Romero J, Rodríguez BL, et al. The immunobiology of the receptor of advanced glycation end-products: trends and challenges. Immunobiology 2013; 218(5): 790-7.
Rojas A, Figueroa H, Morales E. Fueling inflammation at tumor microenvironment: the role of multiligand/RAGE axis. Carcinogenesis 2010; 31(3): 334-41.
Kwak T, Drews-Elger K, Ergonul A, et al. Targeting of RAGE-ligand signaling impairs breast cancer cell invasion and metastasis. Oncogene 2017; 36(11): 1559-72.
Yan SF, Ramasamy R, Schmidt AM. Soluble RAGE: therapy and biomarker in unraveling the RAGE axis in chronic disease and aging. Biochem Pharmacol 2010; 79(10): 1379-86.
Hudson BI, Kalea AZ, Del Mar Arriero M, et al. Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J Biol Chem 2008; 283(49): 34457-46.
Hofmann MA, Drury S, Fu C, et al. RAGE mediates a novel proinflammatory axis: A central cell surface receptor for S100/calgranulin polypeptides. Cell 1999; 97(7): 889-901.
Bierhaus A, Schiekofer S, Schwaninger M, et al. Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. Diabetes 2001; 50(12): 2792-808.
Slowik A, Merres J, Elfgen A, et al. Involvement of formyl peptide receptors in receptor for advanced glycation end products (RAGE)--and amyloid beta 1-42-induced signal transduction in glial cells. Mol Neurodegener 2012; 7: 55.
Mastinu A, Premoli M, Maccarinelli G, et al. Melanocortin 4 receptor stimulation improves social deficits in mice through oxytocin pathway. Neuropharmacology 2018; 133: 366-74.
Metz VV, Kojro E, Rat D, et al. Induction of RAGE shedding by activation of G protein-coupled receptors. PLoS One 2012; 7(7): e41823.
Gąsiorowski K, Brokos B, Echeverria V, et al. RAGE-TLR crosstalk sustains chronic inflammation neurodegeneration. Mol Neurobiol 2018; 55(2): 1463-76.
Ibrahim ZA, Amour CL, Phipps S, et al. RAGE and TLRs: relatives, friends or neighbours? Mol Immunol 2013; 56(4): 739-44.
Nogueira-Machado JA, Volpe CM, Veloso SA, et al. HMGB1, TLR and RAGE: A functional tripod that leads to diabetic inflammation. Expert Opin Ther Targets 2011; 15(8): 1023-35.
Sakaguchi M, Murata H, Yamamoto K, et al. TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding. PLoS One 2011; 6(8): e23132.
Bierhaus A, Humpert PM, Morcos M, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 2005; 83(11): 876-86.
Leclerc E, Fritz G, Vetter SW, et al. Binding of S100 proteins to RAGE: An update. Biochim Biophys Acta 2009; 1793(6): 993-1007.
Fritz G. RAGE: a single receptor fits multiple ligands. Trends Biochem Sci 2011; 36(12): 625-32.
Koch M, Chitayat S, Dattilo BM, et al. Structural basis for ligand recognition and activation of RAGE. Structure 2010; 18(10): 1342-52.
Kuhla A, Norden J, Abshagen K, et al. RAGE blockade and hepatic microcirculation in experimental endotoxaemic liver failure. Br J Surg 2013; 100(9): 1229-39.
Xu X, Chen H, Zhu X, et al. S100A9 promotes human lung fibroblast cells activation through receptor for advanced glycation end-product-mediated extracellular-regulated kinase 1/2, mitogen-activated protein-kinase and nuclear factor-κB-dependent pathways. Clin Exp Immunol 2013; 173(3): 523-35.
Kokkola R, Li J, Sundberg E, et al. Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis Rheum 2003; 48(7): 2052-8.
Musumeci D, Roviello GN, Montesarchio D. An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies. Pharmacol Ther 2014; 141(3): 347-57.
Hearst SM, Walker LR, Shao Q, et al. The design and delivery of a thermally responsive peptide to inhibit S100B-mediated neurodegeneration. Neuroscience 2011; 197: 369-80.
Arumugam T, Ramachandran V, Gomez SB, et al. S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis. Clin Cancer Res 2012; 18(16): 4356-64.
Putranto EW, Murata H, Yamamoto K, et al. Inhibition of RAGE signaling through the intracellular delivery of inhibitor peptides by PEI cationization. Int J Mol Med 2013; 32(4): 938-44.
Zhou B, Rothlein R, Shen J, et al. TTP4000, a soluble fusion protein inhibitor of receptor for advanced glycation end products (RAGE) is an effective therapy in animal models of Alzheimer’s disease. FASEB J (Meeting Abstract Supplement) 2 2013; 27: 803-1.
Takeuchi A, Yamamoto Y, Munesue S, et al. Low molecular weight heparin suppresses receptor for advanced glycation end products-mediated expression of malignant phenotype in human fibrosarcoma cells. Cancer Sci 2013; 104(6): 740-9.
Xu D, Young JH, Krahn JM, et al. Stable RAGE-heparan sulfate complexes are essential for signal transduction. SCS Chem Biol 2013; 8(7): 1611-20.
Zhang J, Xu X, Rao NV, et al. Novel sulfated polysaccharides disrupt cathelicidins, inhibit RAGE and reduce cutaneous inflammation in a mouse model of rosacea. PLoS One 2011; 6(2): e16658.
Sabbagh MN, Agro A, Bell J, et al. PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease. Alzheimer Dis Assoc Disord 2011; 25(3): 206-12.
Galasko D, Bell J, Mancuso JY, et al. Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease. Neurology 2014; 82(17): 1536-42.
Burstein AH, Grimes I, Galasko DR, et al. Effect of TTP488 in patients with mild to moderate Alzheimer’s disease. BMC Neurol 2014; 14: 12.
Burstein AH, Sabbagh M, Andrews R, et al. Development of azeliragon, an oral small molecule antagonist of the receptor for advanced glycation endproducts, for the potential slowing of loss of cognition in mild Alzheimer’s disease. J Prev Alzheimers Dis 2018; 5(2): 149-54.
Han YT, Choi GI, Son D, et al. Ligand-based design, synthesis, and biological evaluation of 2-aminopyrimidines, a novel series of receptor for advanced glycation end products (RAGE) inhibitors. J Med Chem 2012; 55(21): 9120-35.
Han YT, Kim K, Choi GI, et al. Pyrazole-5-carboxamides, novel inhibitors of receptor for advanced glycation end products (RAGE). Eur J Med Chem 2014; 79: 128-42.
Liu XP, Pang YJ, Zhu WW, et al. Benazepril, an angiotensin-converting enzyme inhibitor, alleviates renal injury in spontaneously hypertensive rats by inhibiting advanced glycation end-product-mediated pathways. Clin Exp Pharmacol Physiol 2009; 36(3): 287-96.
Goel R, Bhat SA, Hanif K, et al. Perindopril attenuates Lipopolysaccharide-Induced amyloidogenesis and memory impairment by suppression of oxidative stress and RAGE activation. ACS Chem Neurosci 2016; 7(2): 206-17.
Chiou JW, Fy B, Chou RH, et al. Blocking the interactions between calcium-bound S100A12 protein and the V domain of RAGE using Tranilast. PLoS One 2016; 11(9): e0162000.
Huang YK, Chou RH, Yu C. Tranilast blocks the interaction between the protein S100A11 and receptor for advanced glycation end products (RAGE) V domain and inhibits cell proliferation. J Biol Chem 2016; 291(27): 14300-10.
Mastinu A, Pira M, Pani L, et al. NESS038C6, a novel selective CB1 antagonist agent with anti-obesity activity and improved molecular profile. Behav Brain Res 2012; 234(2): 192-204.
Yousefnia S, Momenzadeh S, Seyed Forootan F, et al. The influence of peroxisome proliferator-activated receptor γ (PPARγ) ligands on cancer cell tumorigenicity. Gene 2018; 649: 14-22.
Yang Y, Zhao LH, Huang B, et al. Pioglitazone, a PPARγ agonist, inhibits growth and invasion of human hepatocellular carcinoma via blockade of the rage signaling. Mol Carcinog 2015; 54(12): 1584-95.
Kim YS, Lee YM, Kim CS, et al. Inhibitory effect of KIOM-79, a new herbal prescription, on AGEs formation and expression of type IV collagen and TGF-β1 in STZ-induced diabetic rats. Korean J Pharmacogn 2006; 37: 103-9.
Kim YS, Jung DH, Kim NH, et al. KIOM-79 inhibits high glucose or AGEs-induced VEGF expression in human retinal pigment epithelial cells. J Ethnopharmacol 2007; 112(1): 166-72.
Jung DH, Kim YS, Kim JS. KIOM-79 prevents S100b-induced TGF-β1 and fibronectin expression in mouse mesangial cells. J Ethnopharmacol 2009; 125(3): 374-9.
Hong Y, An Z. Hesperidin attenuates learning and memory deficits in APP/PS1 mice through activation of Akt/Nrf2 signaling and inhibition of RAGE/NF-κB signaling. Arch Pharm Res 2018; 41(6): 655-63.
Cui L, Cai Y, Cheng W, et al. A novel, multi-target natural drug candidate, matrine, improves cognitive deficits in alzheimer’s disease transgenic mice by inhibiting aβ aggregation and blocking the RAGE/Aβ Axis. Mol Neurobiol 2017; 54(3): 1939-52.
Liu ZW, Wang JK, Qiu C, et al. Matrine pretreatment improves cardiac function in rats with diabetic cardiomyopathy via suppressing ROS/TLR-4 signaling pathway. Acta Pharmacol Sin 2015; 36(3): 323-33.
El-Far A, Munesue S, Harashima A, et al. In vitro anticancer effects of a RAGE inhibitor discovered using a structure-based drug design system. Oncol Lett 2018; 15(4): 4627-34.
Kaida Y, Fukami K, Matsui T, et al. DNA aptamer raised against ages blocks the progression of experimental diabetic nephropathy. Diabetes 2013; 62(9): 3241-50.
Ojima A, Oda E, Higashimoto Y, et al. DNA aptamer raised against advanced glycation end products inhibits neointimal hyperplasia in balloon-injured rat carotid arteries. Int J Cardiol 2014; 171(3): 443-6.
Ojima A, Matsui T, Maeda S, et al. DNA aptamer raised against advanced glycation end products inhibits melanoma growth in nude mice. Lab Invest 2014; 94(4): 422-9.
Ojima A, Matsui T, Nakamura N, et al. DNA aptamer raised against advanced glycation end products (AGEs) improves glycemic control and decreases adipocyte size in fructose-fed rats by suppressing AGE-RAGE axis. Horm Metab Res 2015; 47(4): 253-8.
Taguchi K, Yamagishi S, Yokoro M, et al. RAGE-aptamer attenuates deoxycorticosterone acetate/salt-induced renal injury in mice. Sci Rep 2018; 8(1): 2686.
Nakamara N, Matsui T, Ishibashi Y, et al. RAGE-aptamer attenuates the growth and liver metastasis of malignant melanoma in nude mice. Mol Med 2017; 23: 295-306.
Toure F, Fritz G, Li Q, et al. Formin mDia1 mediates vascular remodeling via integration of oxidative and signal transduction pathways. Circ Res 2012; 110(10): 1279-93.
Manigrasso MB, Pan J, Rai V, et al. Small molecule inhibition of ligand-stimulated RAGE-DIAPH1 signal transduction. Sci Rep 2016; 6: 22450.
Xue J, Manigrasso M, Scalabrin M, et al. Change in the molecular dimension of a RAGE-Ligand complex triggers RAGE signaling. Structure 2016; 24(9): 1509-22.
Sakaguchi M, Kinoshita R, Putranto EW, et al. Signal diversity of receptor for advanced glycation end products. Acta Med Okayama 2017; 71(6): 459-65.
Oczypok EA, Perkins TN, Oury TD. All the “RAGE” in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses. Paediatr Respir Rev 2017; 23: 40-9.
Wolf L, Herr C, Niederstraßer J, et al. Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke. PLoS One 2017; 12(7): e0180092.
Wu S, Mao L, Li Y, et al. RAGE may act as a tumour suppressor to regulate lung cancer development. Gene 2018; 651: 86-93.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 19 August, 2018
Page: [340 - 346]
Pages: 7
DOI: 10.2174/1389450119666180820105956
Price: $65

Article Metrics

PDF: 62
HTML: 14