ENTRY hsa04933 Pathway NAME AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human) DESCRIPTION Advanced glycation end products (AGEs) are a complex group of compounds produced through the non-enzymatic glycation and oxidation of proteins, lipids and nucleic acids, primarily due to aging and under certain pathologic condition such as huperglycemia. Some of the best chemically characterized AGEs include N-epsilon-carboxy-methyl-lysine (CML), N-epsilon-carboxy-ethyl-lysine (CEL), and Imidazolone. The major receptor for AGEs, known as receptor for advanced glycation end products (RAGE or AGER), belongs to the immunoglobulin superfamily and has been described as a pattern recognition receptor. AGE/RAGE signaling elicits activation of multiple intracellular signal pathways involving NADPH oxidase, protein kinase C, and MAPKs, then resulting in NF-kappaB activity. NF-kappa B promotes the expression of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha and a variety of atherosclerosis-related genes, including VCAM-1, tissue factor, VEGF, and RAGE. In addition, JAK-STAT-mediated and PI3K-Akt-dependent pathways are induced via RAGE, which in turn participate in cell proliferation and apoptosis respectively. Hypoxia-mediated induction of Egr-1 was also shown to require the AGE-RAGE interaction. The results of these signal transductions have been reported to be the possible mechanism that initates diabetic complications. CLASS Human Diseases; Endocrine and metabolic disease PATHWAY_MAP hsa04933 AGE-RAGE signaling pathway in diabetic complications DRUG D12654 Emapticap pegol (INN) DBLINKS GO: 1904603 ORGANISM Homo sapiens (human) [GN:hsa] GENE 10000 AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1] 1019 CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22] 1027 CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624] 110117499 P3R3URF-PIK3R3; P3R3URF-PIK3R3 readthrough [KO:K02649] 113026 PLCD3; phospholipase C delta 3 [KO:K05857] [EC:3.1.4.11] 1277 COL1A1; collagen type I alpha 1 chain [KO:K06236] 1278 COL1A2; collagen type I alpha 2 chain [KO:K06236] 1281 COL3A1; collagen type III alpha 1 chain [KO:K19720] 1282 COL4A1; collagen type IV alpha 1 chain [KO:K06237] 1284 COL4A2; collagen type IV alpha 2 chain [KO:K06237] 1285 COL4A3; collagen type IV alpha 3 chain [KO:K06237] 1286 COL4A4; collagen type IV alpha 4 chain [KO:K06237] 1287 COL4A5; collagen type IV alpha 5 chain [KO:K06237] 1288 COL4A6; collagen type IV alpha 6 chain [KO:K06237] 1432 MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24] 1536 CYBB; cytochrome b-245 beta chain [KO:K21421] [EC:1.-.-.-] 1729 DIAPH1; diaphanous related formin 1 [KO:K05740] 177 AGER; advanced glycosylation end-product specific receptor [KO:K19722] 183 AGT; angiotensinogen [KO:K09821] 185 AGTR1; angiotensin II receptor type 1 [KO:K04166] 1906 EDN1; endothelin 1 [KO:K16366] 1958 EGR1; early growth response 1 [KO:K09203] 207 AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1] 208 AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1] 2152 F3; coagulation factor III, tissue factor [KO:K03901] 2277 VEGFD; vascular endothelial growth factor D [KO:K05449] 2308 FOXO1; forkhead box O1 [KO:K07201] 23236 PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11] 2335 FN1; fibronectin 1 [KO:K05717] 27035 NOX1; NADPH oxidase 1 [KO:K08008] 3265 HRAS; HRas proto-oncogene, GTPase [KO:K02833] 3383 ICAM1; intercellular adhesion molecule 1 [KO:K06490] 3552 IL1A; interleukin 1 alpha [KO:K04383] 3553 IL1B; interleukin 1 beta [KO:K04519] 3569 IL6; interleukin 6 [KO:K05405] 3576 CXCL8; C-X-C motif chemokine ligand 8 [KO:K10030] 3717 JAK2; Janus kinase 2 [KO:K04447] [EC:2.7.10.2] 3725 JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448] 3845 KRAS; KRAS proto-oncogene, GTPase [KO:K07827] 4087 SMAD2; SMAD family member 2 [KO:K04500] 4088 SMAD3; SMAD family member 3 [KO:K23605] 4089 SMAD4; SMAD family member 4 [KO:K04501] 4313 MMP2; matrix metallopeptidase 2 [KO:K01398] [EC:3.4.24.24] 4772 NFATC1; nuclear factor of activated T cells 1 [KO:K04446] 4790 NFKB1; nuclear factor kappa B subunit 1 [KO:K02580] 4846 NOS3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39] 4893 NRAS; NRAS proto-oncogene, GTPase [KO:K07828] 50507 NOX4; NADPH oxidase 4 [KO:K21423] [EC:1.6.3.-] 5054 SERPINE1; serpin family E member 1 [KO:K03982] 51196 PLCE1; phospholipase C epsilon 1 [KO:K05860] [EC:3.1.4.11] 5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153] 5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153] 5292 PIM1; Pim-1 proto-oncogene, serine/threonine kinase [KO:K04702] [EC:2.7.11.1] 5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153] 5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649] 5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649] 5330 PLCB2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11] 5331 PLCB3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11] 5332 PLCB4; phospholipase C beta 4 [KO:K05858] [EC:3.1.4.11] 5333 PLCD1; phospholipase C delta 1 [KO:K05857] [EC:3.1.4.11] 5335 PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11] 5336 PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:3.1.4.11] 5578 PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13] 5579 PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13] 5580 PRKCD; protein kinase C delta [KO:K06068] [EC:2.7.11.13] 5581 PRKCE; protein kinase C epsilon [KO:K18050] [EC:2.7.11.13] 5590 PRKCZ; protein kinase C zeta [KO:K18952] [EC:2.7.11.13] 5594 MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24] 5595 MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24] 5599 MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24] 5600 MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24] 5601 MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24] 5602 MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24] 5603 MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24] 581 BAX; BCL2 associated X, apoptosis regulator [KO:K02159] 5879 RAC1; Rac family small GTPase 1 [KO:K04392] 595 CCND1; cyclin D1 [KO:K04503] 596 BCL2; BCL2 apoptosis regulator [KO:K02161] 5970 RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735] 6300 MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24] 6347 CCL2; C-C motif chemokine ligand 2 [KO:K14624] 6401 SELE; selectin E [KO:K06494] 6772 STAT1; signal transducer and activator of transcription 1 [KO:K11220] 6774 STAT3; signal transducer and activator of transcription 3 [KO:K04692] 6776 STAT5A; signal transducer and activator of transcription 5A [KO:K11223] 6777 STAT5B; signal transducer and activator of transcription 5B [KO:K11224] 7040 TGFB1; transforming growth factor beta 1 [KO:K13375] 7042 TGFB2; transforming growth factor beta 2 [KO:K13376] 7043 TGFB3; transforming growth factor beta 3 [KO:K13377] 7046 TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:2.7.11.30] 7048 TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:2.7.11.30] 7056 THBD; thrombomodulin [KO:K03907] 7124 TNF; tumor necrosis factor [KO:K03156] 7412 VCAM1; vascular cell adhesion molecule 1 [KO:K06527] 7422 VEGFA; vascular endothelial growth factor A [KO:K05448] 7423 VEGFB; vascular endothelial growth factor B [KO:K16858] 7424 VEGFC; vascular endothelial growth factor C [KO:K05449] 836 CASP3; caspase 3 [KO:K02187] [EC:3.4.22.56] 84812 PLCD4; phospholipase C delta 4 [KO:K05857] [EC:3.1.4.11] 8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649] 998 CDC42; cell division cycle 42 [KO:K04393] COMPOUND C00031 D-Glucose C00076 Calcium cation C00165 Diacylglycerol C00195 N-Acylsphingosine C01245 D-myo-Inositol 1,4,5-trisphosphate C21011 [Protein]-N(epsilon)-(carboxymethyl)lysine C21012 [Protein]-N(epsilon)-(carboxyethyl)lysine C21013 [Protein]-pyrraline C21014 [Protein]-pentosidine REFERENCE PMID:21261520 AUTHORS Kanwar YS, Sun L, Xie P, Liu FY, Chen S TITLE A glimpse of various pathogenetic mechanisms of diabetic nephropathy. JOURNAL Annu Rev Pathol 6:395-423 (2011) DOI:10.1146/annurev.pathol.4.110807.092150 REFERENCE PMID:21111800 AUTHORS Yamagishi S TITLE Role of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) in vascular damage in diabetes. JOURNAL Exp Gerontol 46:217-24 (2011) DOI:10.1016/j.exger.2010.11.007 REFERENCE PMID:23961320 AUTHORS Roy B TITLE Biomolecular basis of the role of diabetes mellitus in osteoporosis and bone fractures. JOURNAL World J Diabetes 4:101-13 (2013) DOI:10.4239/wjd.v4.i4.101 REFERENCE PMID:22558488 AUTHORS Hegab Z, Gibbons S, Neyses L, Mamas MA TITLE Role of advanced glycation end products in cardiovascular disease. JOURNAL World J Cardiol 4:90-102 (2012) DOI:10.4330/wjc.v4.i4.90 REFERENCE PMID:19404313 AUTHORS Calcutt NA, Cooper ME, Kern TS, Schmidt AM TITLE Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. JOURNAL Nat Rev Drug Discov 8:417-29 (2009) DOI:10.1038/nrd2476 REFERENCE PMID:11180401 AUTHORS Huang JS, Guh JY, Chen HC, Hung WC, Lai YH, Chuang LY TITLE Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. JOURNAL J Cell Biochem 81:102-13 (2001) DOI:10.1002/1097-4644(20010401)81:1<102::AID-JCB1027>3.0.CO;2-Y REFERENCE PMID:21680901 AUTHORS Meloche J, Paulin R, Courboulin A, Lambert C, Barrier M, Bonnet P, Bisserier M, Roy M, Sussman MA, Agharazii M, Bonnet S TITLE RAGE-dependent activation of the oncoprotein Pim1 plays a critical role in systemic vascular remodeling processes. JOURNAL Arterioscler Thromb Vasc Biol 31:2114-24 (2011) DOI:10.1161/ATVBAHA.111.230573 REFERENCE PMID:11684565 AUTHORS Guh JY, Huang JS, Chen HC, Hung WC, Lai YH, Chuang LY TITLE Advanced glycation end product-induced proliferation in NRK-49F cells is dependent on the JAK2/STAT5 pathway and cyclin D1. JOURNAL Am J Kidney Dis 38:1096-104 (2001) DOI:10.1053/ajkd.2001.28616 REFERENCE PMID:16894049 AUTHORS Goldin A, Beckman JA, Schmidt AM, Creager MA TITLE Advanced glycation end products: sparking the development of diabetic vascular injury. JOURNAL Circulation 114:597-605 (2006) DOI:10.1161/CIRCULATIONAHA.106.621854 REFERENCE PMID:21590515 AUTHORS Zong H, Ward M, Stitt AW TITLE AGEs, RAGE, and diabetic retinopathy. JOURNAL Curr Diab Rep 11:244-52 (2011) DOI:10.1007/s11892-011-0198-7 REFERENCE PMID:21440603 AUTHORS Yamagishi S, Maeda S, Matsui T, Ueda S, Fukami K, Okuda S TITLE Role of advanced glycation end products (AGEs) and oxidative stress in vascular complications in diabetes. JOURNAL Biochim Biophys Acta 1820:663-71 (2012) DOI:10.1016/j.bbagen.2011.03.014 REFERENCE PMID:23776698 AUTHORS Shi L, Yu X, Yang H, Wu X TITLE Advanced glycation end products induce human corneal epithelial cells apoptosis through generation of reactive oxygen species and activation of JNK and p38 MAPK pathways. JOURNAL PLoS One 8:e66781 (2013) DOI:10.1371/journal.pone.0066781 REFERENCE PMID:17005604 AUTHORS Alikhani M, Maclellan CM, Raptis M, Vora S, Trackman PC, Graves DT TITLE Advanced glycation end products induce apoptosis in fibroblasts through activation of ROS, MAP kinases, and the FOXO1 transcription factor. JOURNAL Am J Physiol Cell Physiol 292:C850-6 (2007) DOI:10.1152/ajpcell.00356.2006 REFERENCE PMID:20300563 AUTHORS Alikhani M, Roy S, Graves DT TITLE FOXO1 plays an essential role in apoptosis of retinal pericytes. JOURNAL Mol Vis 16:408-15 (2010) REFERENCE PMID:20470857 AUTHORS Sheikpranbabu S, Haribalaganesh R, Lee KJ, Gurunathan S TITLE Pigment epithelium-derived factor inhibits advanced glycation end products-induced retinal vascular permeability. JOURNAL Biochimie 92:1040-51 (2010) DOI:10.1016/j.biochi.2010.05.004 REFERENCE PMID:18922799 AUTHORS Hudson BI, Kalea AZ, Del Mar Arriero M, Harja E, Boulanger E, D'Agati V, Schmidt AM TITLE Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. JOURNAL J Biol Chem 283:34457-68 (2008) DOI:10.1074/jbc.M801465200 REFERENCE PMID:11375353 AUTHORS Yeh CH, Sturgis L, Haidacher J, Zhang XN, Sherwood SJ, Bjercke RJ, Juhasz O, Crow MT, Tilton RG, Denner L TITLE Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. JOURNAL Diabetes 50:1495-504 (2001) DOI:10.2337/diabetes.50.6.1495 REFERENCE PMID:12709399 AUTHORS Li JH, Huang XR, Zhu HJ, Oldfield M, Cooper M, Truong LD, Johnson RJ, Lan HY TITLE Advanced glycation end products activate Smad signaling via TGF-beta-dependent and independent mechanisms: implications for diabetic renal and vascular disease. JOURNAL FASEB J 18:176-8 (2004) DOI:10.1096/fj.02-1117fje REFERENCE PMID:18323529 AUTHORS Chang JS, Wendt T, Qu W, Kong L, Zou YS, Schmidt AM, Yan SF TITLE Oxygen deprivation triggers upregulation of early growth response-1 by the receptor for advanced glycation end products. JOURNAL Circ Res 102:905-13 (2008) DOI:10.1161/CIRCRESAHA.107.165308 REFERENCE PMID:15569303 AUTHORS Fukami K, Ueda S, Yamagishi S, Kato S, Inagaki Y, Takeuchi M, Motomiya Y, Bucala R, Iida S, Tamaki K, Imaizumi T, Cooper ME, Okuda S TITLE AGEs activate mesangial TGF-beta-Smad signaling via an angiotensin II type I receptor interaction. JOURNAL Kidney Int 66:2137-47 (2004) DOI:10.1111/j.1523-1755.2004.66004.x REL_PATHWAY hsa04010 MAPK signaling pathway hsa04020 Calcium signaling pathway hsa04110 Cell cycle hsa04151 PI3K-Akt signaling pathway hsa04350 TGF-beta signaling pathway hsa04614 Renin-angiotensin system hsa04630 JAK-STAT signaling pathway KO_PATHWAY ko04933 ///