KEGG   PATHWAY: oas04933
Entry
oas04933                    Pathway                                
Name
AGE-RAGE signaling pathway in diabetic complications - Ovis aries (sheep)
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
oas04933  AGE-RAGE signaling pathway in diabetic complications
oas04933

Other DBs
GO: 1904603
Organism
Ovis aries (sheep) [GN:oas]
Gene
554322  TGFB2; transforming growth factor beta-2 proprotein isoform X2 [KO:K13376]
554323  TGFB3; transforming growth factor beta-3 proprotein [KO:K13377]
443417  TGFB1; transforming growth factor beta-1 proprotein precursor [KO:K13375]
554326  TGFBR1; TGF-beta receptor type-1 isoform X2 [KO:K04674] [EC:2.7.11.30]
494191  TGFBR2; TGF-beta receptor type-2 isoform X2 [KO:K04388] [EC:2.7.11.30]
101114231  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
443169  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
443171  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
100127219  CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624]
100216462  FN1; fibronectin isoform X4 [KO:K05717]
443483  COL1A1; collagen alpha-1(I) chain [KO:K06236]
443512  COL1A2; collagen alpha-2(I) chain [KO:K06236]
100101231  COL3A1; collagen alpha-1(III) chain [KO:K19720]
101112706  COL4A5; collagen alpha-5(IV) chain [KO:K06237]
101113128  COL4A6; collagen alpha-6(IV) chain isoform X2 [KO:K06237]
101115552  COL4A1; collagen alpha-1(IV) chain [KO:K06237]
101115805  COL4A2; collagen alpha-2(IV) chain isoform X1 [KO:K06237]
101118172  COL4A4; collagen alpha-4(IV) chain isoform X1 [KO:K06237]
101102790  COL4A3; collagen alpha-3(IV) chain isoform X1 [KO:K06237]
101119440  AGT; angiotensinogen [KO:K09821]
443107  AGTR1; type-1 angiotensin II receptor [KO:K04166]
101111586  AGER; advanced glycosylation end product-specific receptor isoform X3 [KO:K19722]
100034667  NOX1; NADPH oxidase 1 isoform X1 [KO:K08008]
100036757  CYBB; cytochrome b-245 heavy chain [KO:K21421] [EC:1.-.-.-]
100034665  NOX4; NADPH oxidase 4 isoform X2 [KO:K21423] [EC:1.6.3.-]
101118035  PLCD3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 isoform X1 [KO:K05857] [EC:3.1.4.11]
101111344  PLCD4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 isoform X1 [KO:K05857] [EC:3.1.4.11]
101110367  PLCD1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 isoform X2 [KO:K05857] [EC:3.1.4.11]
101103585  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
101113074  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
101116105  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
101106864  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X9 [KO:K05858] [EC:3.1.4.11]
101103341  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
101122126  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 isoform X1 [KO:K05859] [EC:3.1.4.11]
101105703  PLCE1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 isoform X1 [KO:K05860] [EC:3.1.4.11]
101110074  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
101118410  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
101107639  PRKCD; protein kinase C delta type isoform X1 [KO:K06068] [EC:2.7.11.13]
101110314  PRKCE; protein kinase C epsilon type isoform X2 [KO:K18050] [EC:2.7.11.13]
101122295  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
101115485  MAPK1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
101123008  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
443219  JUN; transcription factor Jun [KO:K04448]
443103  VEGFA; vascular endothelial growth factor A precursor [KO:K05448]
101115840  VEGFB; vascular endothelial growth factor B isoform X2 [KO:K16858]
101105629  VEGFC; vascular endothelial growth factor C isoform X1 [KO:K05449]
101102873  VEGFD; vascular endothelial growth factor D [KO:K05449]
101120093  C-C motif chemokine 2 [KO:K14624]
100381267  SERPINE1; plasminogen activator inhibitor 1 precursor [KO:K03982]
443127  SELE; E-selectin [KO:K06494]
101113636  vascular cell adhesion protein 1 [KO:K06527]
101114226  vascular cell adhesion protein 1-like isoform X1 [KO:K06527]
443045  ICAM1; intercellular adhesion molecule 1 precursor [KO:K06490]
443115  MMP2; 72 kDa type IV collagenase precursor [KO:K01398] [EC:3.4.24.24]
443404  IL1A; interleukin-1 alpha precursor [KO:K04383]
443539  IL1B; interleukin-1 beta precursor [KO:K04519]
443406  IL6; interleukin-6 precursor [KO:K05405]
443418  CXCL8; interleukin-8 precursor [KO:K10030]
443540  TNF; tumor necrosis factor [KO:K03156]
101118918  F3; tissue factor [KO:K03901]
443498  EDN1; endothelin-1 precursor [KO:K16366]
101103256  THBD; thrombomodulin [KO:K03907]
100194428  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100217411  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
101116223  MAPK11; mitogen-activated protein kinase 11 isoform X2 [KO:K04441] [EC:2.7.11.24]
101115956  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
101102191  RELA; transcription factor p65 [KO:K04735]
101108228  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X2 [KO:K02580]
101116201  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101120826  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
101120665  MAPK10; mitogen-activated protein kinase 10 isoform X2 [KO:K04440] [EC:2.7.11.24]
101106682  DIAPH1; protein diaphanous homolog 1 [KO:K05740]
100101233  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
101102792  CDC42; cell division control protein 42 homolog [KO:K04393]
114108599  cell division control protein 42 homolog [KO:K04393]
101104357  HRAS; GTPase HRas isoform X1 [KO:K02833]
114114919  GTPase HRas-like [KO:K02833]
101114005  KRAS; GTPase KRas isoform X1 [KO:K07827]
101102438  NRAS; GTPase NRas [KO:K07828]
101109759  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
101110015  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101117348  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922] [EC:2.7.1.153]
101123247  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101111546  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X2 [KO:K02649]
101121455  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
101118462  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
101119242  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100294652  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
443077  NOS3; nitric oxide synthase 3 isoform X1 [KO:K13242] [EC:1.14.13.39]
101107877  FOXO1; forkhead box protein O1 [KO:K07201]
101119602  BCL2; apoptosis regulator Bcl-2 isoform X1 [KO:K02161]
443059  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
443031  CASP3; caspase-3 isoform X1 [KO:K02187] [EC:3.4.22.56]
101113909  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
100294659  STAT3; signal transducer and activator of transcription 3 isoform X10 [KO:K04692]
100272002  PIM1; serine/threonine-protein kinase pim-1 [KO:K04702] [EC:2.7.11.1]
101108097  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X6 [KO:K04446]
100307049  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
443419  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
101122961  STAT5B; signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
100144763  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
100144756  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
443547  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
oas04010  MAPK signaling pathway
oas04020  Calcium signaling pathway
oas04110  Cell cycle
oas04151  PI3K-Akt signaling pathway
oas04350  TGF-beta signaling pathway
oas04614  Renin-angiotensin system
oas04630  JAK-STAT signaling pathway
KO pathway
ko04933   
LinkDB

DBGET integrated database retrieval system