KEGG   PATHWAY: pcoo04933
Entry
pcoo04933                   Pathway                                
Name
AGE-RAGE signaling pathway in diabetic complications - Puma concolor (puma)
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
pcoo04933  AGE-RAGE signaling pathway in diabetic complications
pcoo04933

Other DBs
GO: 1904603
Organism
Puma concolor (puma) [GN:pcoo]
Gene
112864785  TGFB2; transforming growth factor beta-2 [KO:K13376]
112855350  TGFB3; transforming growth factor beta-3 [KO:K13377]
112850697  TGFB1; transforming growth factor beta-1 [KO:K13375]
112851426  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
112850049  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
112868176  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
112855310  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
112868129  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
112867392  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
112866897  FN1; fibronectin [KO:K05717]
112852624  collagen alpha-1(I) chain-like [KO:K06236]
112866968  COL1A2; collagen alpha-2(I) chain [KO:K06236]
112848503  COL3A1; collagen alpha-1(III) chain [KO:K19720]
112870677  collagen alpha-6(IV) chain-like [KO:K06237]
112870827  COL4A5; collagen alpha-5(IV) chain isoform X1 [KO:K06237]
112860738  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
112860739  COL4A1; collagen alpha-1(IV) chain [KO:K06237]
112867287  COL4A4; collagen alpha-4(IV) chain [KO:K06237]
112867295  collagen alpha-3(IV) chain-like [KO:K06237]
112851576  AGT; LOW QUALITY PROTEIN: angiotensinogen [KO:K09821]
112849615  AGTR1; type-1 angiotensin II receptor [KO:K04166]
112853779  AGER; advanced glycosylation end product-specific receptor [KO:K19722]
112870702  NOX1; NADPH oxidase 1 [KO:K08008]
112871449  cytochrome b-245 heavy chain [KO:K21421] [EC:1.-.-.-]
112865000  NOX4; NADPH oxidase 4 isoform X1 [KO:K21423] [EC:1.6.3.-]
112849616  PLCD1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 isoform X1 [KO:K05857] [EC:3.1.4.11]
112853968  PLCD3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 [KO:K05857] [EC:3.1.4.11]
112867017  PLCD4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 [KO:K05857] [EC:3.1.4.11]
112855622  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
112869362  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
112869587  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
112851908  PLCB3; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
112869500  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
112857487  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
112854425  PLCE1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 isoform X1 [KO:K05860] [EC:3.1.4.11]
112864470  PRKCA; LOW QUALITY PROTEIN: protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
112853117  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
112852480  PRKCD; protein kinase C delta type [KO:K06068] [EC:2.7.11.13]
112869711  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
112861986  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
112856394  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
112870302  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
112872218  JUN; transcription factor AP-1 [KO:K04448]
112862794  VEGFA; vascular endothelial growth factor A [KO:K05448]
112851906  VEGFB; vascular endothelial growth factor B [KO:K16858]
112869936  VEGFC; vascular endothelial growth factor C [KO:K05449]
112871693  VEGFD; vascular endothelial growth factor D [KO:K05449]
112852822  C-C motif chemokine 2 [KO:K14624]
112860099  SERPINE1; plasminogen activator inhibitor 1 [KO:K03982]
112863106  SELE; E-selectin [KO:K06494]
112848408  VCAM1; vascular cell adhesion protein 1 isoform X1 [KO:K06527]
112852260  ICAM1; intercellular adhesion molecule 1 [KO:K06490]
112857297  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
112864204  IL1A; interleukin-1 alpha [KO:K04383]
112864068  IL1B; interleukin-1 beta [KO:K04519]
112866659  IL6; interleukin-6 [KO:K05405]
112858506  CXCL8; interleukin-8 [KO:K10030]
112853630  TNF; tumor necrosis factor [KO:K03156]
112848721  F3; tissue factor [KO:K03901]
112853681  EDN1; endothelin-1 [KO:K16366]
112869324  THBD; thrombomodulin [KO:K03907]
112862836  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
112862837  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
112863384  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
112851941  RELA; transcription factor p65 [KO:K04735]
112858048  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
112859092  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
112854846  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
112861322  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
112860965  DIAPH1; LOW QUALITY PROTEIN: protein diaphanous homolog 1 [KO:K05740]
112859959  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
112872162  CDC42; cell division control protein 42 homolog [KO:K04393]
112868012  KRAS; GTPase KRas isoform X1 [KO:K07827]
112848478  NRAS; GTPase NRas [KO:K07828]
112849397  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
112849524  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
112848856  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
112861619  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
112868847  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
112863208  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
112851313  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
112866504  NOS3; LOW QUALITY PROTEIN: nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
112860838  FOXO1; forkhead box protein O1 [KO:K07201]
112868295  BCL2; LOW QUALITY PROTEIN: apoptosis regulator Bcl-2 [KO:K02161]
112870035  CASP3; caspase-3 isoform X1 [KO:K02187] [EC:3.4.22.56]
112868696  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
112853996  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
112869860  STAT1; signal transducer and activator of transcription 1-alpha/beta isoform X1 [KO:K11220]
112853998  signal transducer and activator of transcription 5A [KO:K11223]
112863780  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
112860657  EGR1; early growth response protein 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
Related
pathway
pcoo04010  MAPK signaling pathway
pcoo04020  Calcium signaling pathway
pcoo04110  Cell cycle
pcoo04151  PI3K-Akt signaling pathway
pcoo04350  TGF-beta signaling pathway
pcoo04614  Renin-angiotensin system
pcoo04630  JAK-STAT signaling pathway
KO pathway
ko04933   
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