KEGG   PATHWAY: hsa04933Help
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
BRITE hierarchy
Pathway map
hsa04933  AGE-RAGE signaling pathway in diabetic complications
hsa04933

Ortholog table
Disease
H01456  Diabetic nephropathy
H01457  Diabetic retinopathy
H01459  Diabetic neuropathy
H01593  Osteoporosis
Other DBs
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:K04500]
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
  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
  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
  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
  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
  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
  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
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
KO pathway
ko04933   

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