KEGG   PATHWAY: map04933
Entry
map04933                    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
Human Diseases; Endocrine and metabolic disease
Pathway map
map04933  AGE-RAGE signaling pathway in diabetic complications
map04933

Other DBs
GO: 1904603
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
Related
pathway
map04010  MAPK signaling pathway
map04020  Calcium signaling pathway
map04110  Cell cycle
map04151  PI3K-Akt signaling pathway
map04350  TGF-beta signaling pathway
map04614  Renin-angiotensin system
map04630  JAK-STAT signaling pathway
KO pathway
ko04933   

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