KEGG   PATHWAY: ko04933Help
Entry
ko04933                     Pathway                                

Name
AGE-RAGE signaling pathway in diabetic complications
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
09160 Human Diseases; 09166 Endocrine and metabolic diseases
BRITE hierarchy
Pathway map
ko04933  AGE-RAGE signaling pathway in diabetic complications
ko04933

Ortholog table
Disease
H01456  Diabetic nephropathy
H01457  Diabetic retinopathy
H01459  Diabetic neuropathy
H01593  Osteoporosis
Other DBs
BSID: 1319775
GO: 1904603
Orthology
K13376  transforming growth factor beta-2
K13377  transforming growth factor beta-3
K13375  transforming growth factor beta-1
K04674  TGF-beta receptor type-1 [EC:2.7.11.30]
K04388  TGF-beta receptor type-2 [EC:2.7.11.30]
K04500  mothers against decapentaplegic homolog 2/3
K04501  mothers against decapentaplegic homolog 4
K06624  cyclin-dependent kinase inhibitor 1B
K05717  fibronectin 1
K06236  collagen, type I, alpha
K19720  collagen, type III, alpha
K06237  collagen, type IV, alpha
K04166  angiotensin II receptor type 1
K19722  receptor for advanced glycosylation end products
K08008  NADPH oxidase 1
K21421  NADPH oxidase 2 [EC:1.-.-.-]
K21423  NADPH oxidase 4 [EC:1.6.3.-]
K05857  phosphatidylinositol phospholipase C, delta [EC:3.1.4.11]
K05858  phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K01116  phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11]
K05859  phosphatidylinositol phospholipase C, gamma-2 [EC:3.1.4.11]
K05860  phosphatidylinositol phospholipase C, epsilon [EC:3.1.4.11]
K02677  classical protein kinase C alpha type [EC:2.7.11.13]
K19662  classical protein kinase C beta type [EC:2.7.11.13]
K06068  novel protein kinase C delta type [EC:2.7.11.13]
K18050  novel protein kinase C epsilon type [EC:2.7.11.13]
K18952  atypical protein kinase C zeta type [EC:2.7.11.13]
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04448  transcription factor AP-1
K05448  vascular endothelial growth factor A
K16858  vascular endothelial growth factor B
K05449  vascular endothelial growth factor C/D
K14624  C-C motif chemokine 2
K03982  plasminogen activator inhibitor 1
K06494  selectin, endothelial cell
K06527  vascular cell adhesion molecule 1
K06490  intercellular adhesion molecule 1
K01398  matrix metalloproteinase-2 (gelatinase A) [EC:3.4.24.24]
K04383  interleukin 1 alpha
K04519  interleukin 1 beta
K05405  interleukin 6
K10030  interleukin 8
K03156  tumor necrosis factor superfamily, member 2
K03901  coagulation factor III (tissue factor)
K16366  endothelin-1
K03907  thrombomodulin
K04441  p38 MAP kinase [EC:2.7.11.24]
K04735  transcription factor p65
K02580  nuclear factor NF-kappa-B p105 subunit
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K05740  diaphanous 1
K04392  Ras-related C3 botulinum toxin substrate 1
K04393  cell division control protein 42
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04456  RAC serine/threonine-protein kinase [EC:2.7.11.1]
K13242  nitric-oxide synthase, endothelial [EC:1.14.13.39]
K07201  forkhead box protein O1
K02161  apoptosis regulator Bcl-2
K02159  apoptosis regulator BAX
K02187  caspase 3 [EC:3.4.22.56]
K04447  Janus kinase 2 [EC:2.7.10.2]
K04692  signal transducer and activator of transcription 3
K04702  proto-oncogene serine/threonine-protein kinase Pim-1 [EC:2.7.11.1]
K04446  nuclear factor of activated T-cells, cytoplasmic 1
K11220  signal transducer and activator of transcription 1
K11223  signal transducer and activator of transcription 5A
K11224  signal transducer and activator of transcription 5B
K04503  G1/S-specific cyclin-D1
K02089  cyclin-dependent kinase 4 [EC:2.7.11.22]
K09203  early growth response protein 1
Compound
C00031  D-Glucose
C00076  Calcium cation
C00165  Diacylglycerol
C00195  N-Acylsphingosine
C01245  D-myo-Inositol 1,4,5-trisphosphate
C02135  Angiotensin II
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
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