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        D11814  Tisotumab vedotin (USAN/INN)
DBLINKS     GO: 1904603
ORGANISM    Homo sapiens (human) [GN:hsa]
GENE        7042  TGFB2; transforming growth factor beta 2 [KO:K13376]
            7043  TGFB3; transforming growth factor beta 3 [KO:K13377]
            7040  TGFB1; transforming growth factor beta 1 [KO:K13375]
            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]
            4087  SMAD2; SMAD family member 2 [KO:K04500]
            4088  SMAD3; SMAD family member 3 [KO:K23605]
            4089  SMAD4; SMAD family member 4 [KO:K04501]
            1027  CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624]
            2335  FN1; fibronectin 1 [KO:K05717]
            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]
            1284  COL4A2; collagen type IV alpha 2 chain [KO:K06237]
            1286  COL4A4; collagen type IV alpha 4 chain [KO:K06237]
            1288  COL4A6; collagen type IV alpha 6 chain [KO:K06237]
            1282  COL4A1; collagen type IV alpha 1 chain [KO:K06237]
            1287  COL4A5; collagen type IV alpha 5 chain [KO:K06237]
            1285  COL4A3; collagen type IV alpha 3 chain [KO:K06237]
            183  AGT; angiotensinogen [KO:K09821]
            185  AGTR1; angiotensin II receptor type 1 [KO:K04166]
            177  AGER; advanced glycosylation end-product specific receptor [KO:K19722]
            27035  NOX1; NADPH oxidase 1 [KO:K08008]
            1536  CYBB; cytochrome b-245 beta chain [KO:K21421] [EC:1.-.-.-]
            50507  NOX4; NADPH oxidase 4 [KO:K21423] [EC:1.6.3.-]
            5333  PLCD1; phospholipase C delta 1 [KO:K05857] [EC:3.1.4.11]
            113026  PLCD3; phospholipase C delta 3 [KO:K05857] [EC:3.1.4.11]
            84812  PLCD4; phospholipase C delta 4 [KO:K05857] [EC:3.1.4.11]
            23236  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]
            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]
            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]
            51196  PLCE1; phospholipase C epsilon 1 [KO:K05860] [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]
            3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
            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]
            2277  VEGFD; vascular endothelial growth factor D [KO:K05449]
            6347  CCL2; C-C motif chemokine ligand 2 [KO:K14624]
            5054  SERPINE1; serpin family E member 1 [KO:K03982]
            6401  SELE; selectin E [KO:K06494]
            7412  VCAM1; vascular cell adhesion molecule 1 [KO:K06527]
            3383  ICAM1; intercellular adhesion molecule 1 [KO:K06490]
            4313  MMP2; matrix metallopeptidase 2 [KO:K01398] [EC:3.4.24.24]
            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]
            7124  TNF; tumor necrosis factor [KO:K03156]
            2152  F3; coagulation factor III, tissue factor [KO:K03901]
            1906  EDN1; endothelin 1 [KO:K16366]
            7056  THBD; thrombomodulin [KO:K03907]
            5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
            6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
            5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
            1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
            5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
            4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
            5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
            5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
            5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
            1729  DIAPH1; diaphanous related formin 1 [KO:K05740]
            5879  RAC1; Rac family small GTPase 1 [KO:K04392]
            998  CDC42; cell division cycle 42 [KO:K04393]
            3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
            3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
            4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
            5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
            5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [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]
            5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
            5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
            8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
            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]
            10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
            4846  NOS3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]
            2308  FOXO1; forkhead box O1 [KO:K07201]
            596  BCL2; BCL2 apoptosis regulator [KO:K02161]
            581  BAX; BCL2 associated X, apoptosis regulator [KO:K02159]
            836  CASP3; caspase 3 [KO:K02187] [EC:3.4.22.56]
            3717  JAK2; Janus kinase 2 [KO:K04447] [EC:2.7.10.2]
            6774  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
            5292  PIM1; Pim-1 proto-oncogene, serine/threonine kinase [KO:K04702] [EC:2.7.11.1]
            4772  NFATC1; nuclear factor of activated T cells 1 [KO:K04446]
            6772  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
            6776  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
            6777  STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
            595  CCND1; cyclin D1 [KO:K04503]
            1019  CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
            1958  EGR1; early growth response 1 [KO:K09203]
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
///
