KEGG PATHWAY: rno04933

PATHWAY: rno04933

Entry

rno04933                    Pathway

Name

AGE-RAGE signaling pathway in diabetic complications - Rattus norvegicus (rat)

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

rno04933

AGE-RAGE signaling pathway in diabetic complications

Other DBs

GO:

1904603

Organism

Rattus norvegicus (rat) [GN:rno]

Gene

81809

Tgfb2; transforming growth factor beta-2 proprotein precursor [KO:K13376]

25717

Tgfb3; transforming growth factor beta-3 proprotein preproprotein [KO:K13377]

59086

Tgfb1; transforming growth factor beta-1 proprotein precursor [KO:K13375]

29591

Tgfbr1; TGF-beta receptor type-1 precursor [KO:K04674] [EC:2.7.11.30]

81810

Tgfbr2; TGF-beta receptor type-2 precursor [KO:K04388] [EC:2.7.11.30]

29357

Smad2; mothers against decapentaplegic homolog 2 [KO:K04500]

25631

Smad3; mothers against decapentaplegic homolog 3 [KO:K23605]

50554

Smad4; mothers against decapentaplegic homolog 4 [KO:K04501]

83571

Cdkn1b; cyclin-dependent kinase inhibitor 1B [KO:K06624]

25661

Fn1; fibronectin precursor [KO:K05717]

84352

Col1a2; collagen alpha-2(I) chain precursor [KO:K06236]

29393

Col1a1; collagen alpha-1(I) chain precursor [KO:K06236]

84032

Col3a1; collagen alpha-1(III) chain precursor [KO:K19720]

290905

Col4a1; collagen alpha-1(IV) chain precursor [KO:K06237]

306628

Col4a2; collagen alpha-2(IV) chain precursor [KO:K06237]

363457

Col4a5; collagen alpha-5(IV) chain precursor [KO:K06237]

363265

Col4a3; collagen alpha-3(IV) chain precursor [KO:K06237]

363458

Col4a6; collagen type IV alpha 6 chain precursor [KO:K06237]

24179

Agt; angiotensinogen precursor [KO:K09821]

24180

Agtr1a; type-1 angiotensin II receptor A [KO:K04166]

81638

Agtr1b; type-1 angiotensin II receptor B [KO:K04166]

81722

Ager; advanced glycosylation end product-specific receptor precursor [KO:K19722]

114243

Nox1; NADPH oxidase 1 [KO:K08008]

66021

Cybb; cytochrome b-245 beta chain [KO:K21421] [EC:1.-.-.-]

85431

Nox4; NADPH oxidase 4 [KO:K21423] [EC:1.6.3.-]

24655

Plcd1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 [KO:K05857] [EC:3.1.4.11]

287745

Plcd3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 [KO:K05857] [EC:3.1.4.11]

140693

Plcd4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 [KO:K05857] [EC:3.1.4.11]

24654

Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]

29322

Plcb3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]

85240

Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]

25031

Plcb4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]

25738

Plcg1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]

29337

Plcg2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]

114633

Plce1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 [KO:K05860] [EC:3.1.4.11]

24680

Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]

25023

Prkcb; protein kinase C beta type isoform 2 [KO:K19662] [EC:2.7.11.13]

170538

Prkcd; protein kinase C delta type [KO:K06068] [EC:2.7.11.13]

29340

Prkce; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]

25522

Prkcz; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]

116590

Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]

50689

Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]

24516

Jun; transcription factor Jun [KO:K04448]

83785

Vegfa; vascular endothelial growth factor A isoform 6 precursor [KO:K05448]

89811

Vegfb; vascular endothelial growth factor B precursor [KO:K16858]

114111

Vegfc; vascular endothelial growth factor C precursor [KO:K05449]

360457

Vegfd; vascular endothelial growth factor D precursor [KO:K05449]

287562

Ccl12; C-C motif chemokine ligand 12 precursor [KO:K14624]

24770

Ccl2; C-C motif chemokine 2 precursor [KO:K14624]

24617

Serpine1; plasminogen activator inhibitor 1 precursor [KO:K03982]

25544

Sele; E-selectin precursor [KO:K06494]

25361

Vcam1; vascular cell adhesion protein 1 precursor [KO:K06527]

25464

Icam1; intercellular adhesion molecule 1 precursor [KO:K06490]

81686

Mmp2; 72 kDa type IV collagenase precursor [KO:K01398] [EC:3.4.24.24]

24493

Il1a; interleukin-1 alpha [KO:K04383]

24494

Il1b; interleukin-1 beta [KO:K04519]

24498

Il6; interleukin-6 precursor [KO:K05405]

24835

Tnf; tumor necrosis factor [KO:K03156]

25584

F3; tissue factor precursor [KO:K03901]

24323

Edn1; endothelin-1 preproprotein [KO:K16366]

83580

Thbd; thrombomodulin precursor [KO:K03907]

81649

Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]

60352

Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]

29513

Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]

689314

Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]

309165

Rela; transcription factor p65 [KO:K04735]

81736

Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 2 [KO:K02580]

25272

Mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]

50658

Mapk9; mitogen-activated protein kinase 9 isoform 2 [KO:K04440] [EC:2.7.11.24]

116554

Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]

307483

Diaph1; protein diaphanous homolog 1 isoform 1 [KO:K05740]

363875

Rac1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]

64465

Cdc42; cell division control protein 42 homolog [KO:K04393]

293621

Hras; GTPase HRas [KO:K02833]

367858

Hrasl1; HRas proto-oncogene, GTPase like 1 [KO:K02833]

24525

Kras; GTPase KRas [KO:K07827]

24605

Nras; GTPase NRas [KO:K07828]

85243

Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]

170911

Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]

366508

Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]

134484121

LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]

25513

Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]

60664

Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]

29741

Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]

24185

Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]

25233

Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]

29414

Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]

24600

Nos3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]

84482

Foxo1; forkhead box protein O1 [KO:K07201]

24224

Bcl2; apoptosis regulator Bcl-2 [KO:K02161]

24887

Bax; apoptosis regulator BAX [KO:K02159]

367149

Bax-ps1; apoptosis regulator BAX-like [KO:K02159]

681314

apoptosis regulator BAX-like [KO:K02159]

25402

Casp3; caspase-3 [KO:K02187] [EC:3.4.22.56]

24514

Jak2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]

25125

Stat3; signal transducer and activator of transcription 3 [KO:K04692]

24649

Pim1; serine/threonine-protein kinase pim-1 [KO:K04702] [EC:2.7.11.1]

100361818

Nfatc1; nuclear factor of activated T-cells, cytoplasmic 1 isoform 1 [KO:K04446]

25124

Stat1; signal transducer and activator of transcription 1-alpha/beta isoform beta [KO:K11220]

24918

Stat5a; signal transducer and activator of transcription 5A [KO:K11223]

25126

Stat5b; signal transducer and activator of transcription 5B [KO:K11224]

58919

Ccnd1; G1/S-specific cyclin-D1 [KO:K04503]

94201

Cdk4; cyclin-dependent kinase 4 isoform 1 [KO:K02089] [EC:2.7.11.22]

24330

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

PMID:21261520

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

PMID:21111800

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

PMID:23961320

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

PMID:22558488

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

PMID:19404313

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

PMID:11180401

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

J Cell Biochem 81:102-13 (2001)
DOI:10.1002/1097-4644(20010401)81:1<102::AID-JCB1027>3.0.CO;2-Y

Reference

PMID:21680901

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

PMID:11684565

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

PMID:16894049

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

PMID:21590515

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

PMID:21440603

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

PMID:23776698

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

PMID:17005604

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

PMID:20300563

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

PMID:20470857

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

PMID:18922799

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

PMID:11375353

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

PMID:12709399

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

PMID:18323529

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

PMID:15569303