Entry Name AGE-RAGE signaling pathway in diabetic complications - Canis lupus familiaris (dog)
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 diseaseBRITE hierarchy
Pathway map cfa04933 AGE-RAGE signaling pathway in diabetic complications
Other DBs Organism Canis lupus familiaris (dog) [GN:
cfa ]
Gene 100856190 PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858 ] [EC:3.1.4.11 ]
119863888 CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393 ]
403168 AGER; advanced glycosylation end product-specific receptor precursor [KO:K19722 ]
403429 CDKN1B; cyclin-dependent kinase inhibitor 1B [KO:K06624 ]
403466 COL4A5; collagen alpha-5(IV) chain precursor [KO:K06237 ]
403476 SERPINE1; plasminogen activator inhibitor 1 precursor [KO:K03982 ]
403496 COL4A1; collagen alpha-1(IV) chain isoform X3 [KO:K06237 ]
403651 COL1A1; collagen alpha-1(I) chain precursor [KO:K06236 ]
403802 VEGFA; vascular endothelial growth factor A isoform 1 precursor [KO:K05448 ]
403824 COL1A2; collagen alpha-2(I) chain precursor [KO:K06236 ]
403840 COL4A6; collagen alpha-6(IV) chain isoform X1 [KO:K06237 ]
403843 COL4A2; collagen alpha-2(IV) chain isoform X1 [KO:K06237 ]
403955 RAC1; ras-related C3 botulinum toxin substrate 1 precursor [KO:K04392 ]
403975 ICAM1; intercellular adhesion molecule 1 precursor [KO:K06490 ]
403982 VCAM1; vascular cell adhesion protein 1 precursor [KO:K06527 ]
403998 TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375 ]
442859 NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580 ]
476034 PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X2 [KO:K05858 ] [EC:3.1.4.11 ]
476036 VEGFB; vascular endothelial growth factor B isoform X1 [KO:K16858 ]
476196 SMAD4; mothers against decapentaplegic homolog 4 isoform X2 [KO:K04501 ]
477085 PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922 ] [EC:2.7.1.153 ]
477160 PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858 ] [EC:3.1.4.11 ]
478835 COL3A1; collagen alpha-1(III) chain isoform X1 [KO:K19720 ]
478910 PLCD4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 isoform X2 [KO:K05857 ] [EC:3.1.4.11 ]
480144 SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500 ]
482932 VEGFC; vascular endothelial growth factor C [KO:K05449 ]
483729 RELA; transcription factor p65 isoform X2 [KO:K04735 ]
483925 NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X3 [KO:K04446 ]
485144 NOX4; NADPH oxidase 4 isoform X1 [KO:K21423 ] [EC:1.6.3.-]
485586 PLCD1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 isoform X1 [KO:K05857 ] [EC:3.1.4.11 ]
485773 PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858 ] [EC:3.1.4.11 ]
485874 PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116 ] [EC:3.1.4.11 ]
486808 PLCE1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 [KO:K05860 ] [EC:3.1.4.11 ]
487235 PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649 ]
488084 PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
488449 STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220 ]
488596 TGFB2; transforming growth factor beta-2 proprotein isoform X3 [KO:K13376 ]
489644 PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922 ] [EC:2.7.1.153 ]
489692 PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859 ] [EC:3.1.4.11 ]
490796 TGFB3; transforming growth factor beta-3 proprotein [KO:K13377 ]
490929 PLCD3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 isoform X1 [KO:K05857 ] [EC:3.1.4.11 ]
490967 STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692 ]
490968 STAT5A; signal transducer and activator of transcription 5A isoform X2 [KO:K11223 ]
490969 STAT5B; signal transducer and activator of transcription 5B isoform X2 [KO:K11224 ]
491749 VEGFD; vascular endothelial growth factor D isoform X2 [KO:K05449 ]
491825 CYBB; cytochrome b-245, beta polypeptide [KO:K21421 ] [EC:1.-.-.-]
609956 PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
610902 SMAD3; mothers against decapentaplegic homolog 3 [KO:K23605 ]
Compound C01245 D-myo-Inositol 1,4,5-trisphosphate
C21011 [Protein]-N(epsilon)-(carboxymethyl)lysine
C21012 [Protein]-N(epsilon)-(carboxyethyl)lysine
Reference Authors Kanwar YS, Sun L, Xie P, Liu FY, Chen S
Title A glimpse of various pathogenetic mechanisms of diabetic nephropathy.
Journal Reference Authors Yamagishi S
Title Role of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) in vascular damage in diabetes.
Journal Reference Authors Roy B
Title Biomolecular basis of the role of diabetes mellitus in osteoporosis and bone fractures.
Journal Reference Authors Hegab Z, Gibbons S, Neyses L, Mamas MA
Title Role of advanced glycation end products in cardiovascular disease.
Journal Reference Authors Calcutt NA, Cooper ME, Kern TS, Schmidt AM
Title Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials.
Journal 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 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 Reference Authors Goldin A, Beckman JA, Schmidt AM, Creager MA
Title Advanced glycation end products: sparking the development of diabetic vascular injury.
Journal Reference Authors Zong H, Ward M, Stitt AW
Title AGEs, RAGE, and diabetic retinopathy.
Journal 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 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 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 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 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 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 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 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 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 Related KO pathway 
