General Information:

Id: 2,088
Diseases: Diabetes mellitus, type II - [OMIM]
Insulin resistance
Mammalia
review
Reference: Schmidt AM et al.(1999) Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ. Res. 84: 489-497 [PMID: 10082470]

Interaction Information:

Comment Elevated flux of metabolites through the polyol pathway results in excess generation of sorbitol, decreased myoinositol uptake, and diminished Na/K ATPase activity and has been suggested as a means of globally perturbing cellular functions in the setting of hyperglycemia.
Formal Description
Interaction-ID: 16822

process

polyol pathway

increases_quantity of

drug/chemical compound

Sorbitol

Comment Elevated flux of metabolites through the polyol pathway results in excess generation of sorbitol, decreased myoinositol uptake, and diminished Na/K ATPase activity and has been suggested as a means of globally perturbing cellular functions in the setting of hyperglycemia.
Formal Description
Interaction-ID: 16823

process

polyol pathway

decreases_activity of

into the cell
Comment Elevated flux of metabolites through the polyol pathway results in excess generation of sorbitol, decreased myoinositol uptake, and diminished Na/K ATPase activity and has been suggested as a means of globally perturbing cellular functions in the setting of hyperglycemia.
Formal Description
Interaction-ID: 16824

process

polyol pathway

decreases_activity of

complex/PPI

Sodium:potassium-exchanging ATPase complex

Comment Elevated flux of metabolites through the polyol pathway results in excess generation of sorbitol, decreased myoinositol uptake, and diminished Na/K ATPase activity and has been suggested as a means of globally perturbing cellular functions in the setting of hyperglycemia.
Formal Description
Interaction-ID: 16825

phenotype

hyperglycemia

increases_activity of

process

polyol pathway

Comment Hyperglycemia-mediated activation of protein kinase C, resulting in recruitment of effector mechanisms causing increased vascular permeability and ameliorating retinopathy, has been demonstrated.
Formal Description
Interaction-ID: 16826

phenotype

hyperglycemia

increases_activity of

gene/protein

Protein kinase C

Comment In the setting of hyperglycemia, nonenzymatic glycoxidation results from the interaction of aldoses, such as glucose, with free amino groups on polypeptides or lipids. Formation of early glycation end products, such as Schiff bases and Amadori products, the best-known of which is hemoglobin A1c, is reversible. Further molecular rearrangements, often involving oxidation, eventuate in the formation of advanced glycation end products (AGEs).
Formal Description
Interaction-ID: 16827

phenotype

hyperglycemia

increases_quantity of

drug/chemical compound

Advanced glycation end-product

Comment In the setting of hyperglycemia, nonenzymatic glycoxidation results from the interaction of aldoses, such as glucose, with free amino groups on polypeptides or lipids. Formation of early glycation end products, such as Schiff bases and Amadori products, the best-known of which is hemoglobin A1c, is reversible. Further molecular rearrangements, often involving oxidation, eventuate in the formation of advanced glycation end products (AGEs).
Formal Description
Interaction-ID: 16828

phenotype

hyperglycemia

increases_quantity of

complex/PPI

Glycated hemoglobin

Comment Once formed, AGE-protein adducts, such as carboxymethyl-lysine and pentosidine linked to polypeptides, are quite stable and, in fact, virtually irreversible. Although there are many other AGE-related chemical structures likely to be present in deposits of AGEs found in the vasculature and other tissues (eg, pyrralines that form as a result of glycation alone), carboxymethyl-lysineprotein adducts are the predominant AGEs present in vivo. For example, carboxymethyl-lysine epitopes are increased at sites of atherosclerotic lesions, especially in patients with concomitant diabetes.
Formal Description
Interaction-ID: 16829

increases_quantity of

drug/chemical compound

N(6)-Carboxymethyllysine

Comment Although AGEs may have been previously considered to be restricted to diabetes, it is now recognized that oxidation alone can lead to AGE formation and AGEs have been identified in atherosclerotic tissues without diabetes.
Formal Description
Interaction-ID: 16837

increases_quantity of

drug/chemical compound

Advanced glycation end-product

Comment In the endothelium, AGEs diminish vascular barrier function, enhance expression of vascular cell adhesion molecule-1 (VCAM-1), quench nitric oxide, and alter the balance of cellular coagulant properties, in part through induction of procoagulant tissue factor.
Formal Description
Interaction-ID: 16838

drug/chemical compound

Advanced glycation end-product

affects_activity of

Comment In the endothelium, AGEs diminish vascular barrier function, enhance expression of vascular cell adhesion molecule-1 (VCAM-1), quench nitric oxide, and alter the balance of cellular coagulant properties, in part through induction of procoagulant tissue factor.
Formal Description
Interaction-ID: 16839

drug/chemical compound

Advanced glycation end-product

increases_expression of

gene/protein

VCAM1

Drugbank entries Show/Hide entries for VCAM1
Comment In the endothelium, AGEs diminish vascular barrier function, enhance expression of vascular cell adhesion molecule-1 (VCAM-1), quench nitric oxide, and alter the balance of cellular coagulant properties, in part through induction of procoagulant tissue factor.
Formal Description
Interaction-ID: 16840

drug/chemical compound

Advanced glycation end-product

affects_quantity of

drug/chemical compound

NO

Comment In the endothelium, AGEs diminish vascular barrier function, enhance expression of vascular cell adhesion molecule-1 (VCAM-1), quench nitric oxide, and alter the balance of cellular coagulant properties, in part through induction of procoagulant tissue factor.
Formal Description
Interaction-ID: 16841

drug/chemical compound

Advanced glycation end-product

affects_activity of

process

coagulation

Comment In the endothelium, AGEs diminish vascular barrier function, enhance expression of vascular cell adhesion molecule-1 (VCAM-1), quench nitric oxide, and alter the balance of cellular coagulant properties, in part through induction of procoagulant tissue factor.
Formal Description
Interaction-ID: 16842

drug/chemical compound

Advanced glycation end-product

increases_expression of

gene/protein

F3

Drugbank entries Show/Hide entries for F3
Comment Analysis of the RAGE promoter shows putative nuclear factor-kB (NF-kB) sites, along with an interferon-gamma response element and nuclear factor-interleukin 6 DNA binding motif. The 3 NF-kappaB sites were analyzed and 2 of them were found to be active and involved in the regulation of RAGE expression.
Formal Description
Interaction-ID: 16843

complex/PPI

NF-kappaB complex

affects_expression of

gene/protein

AGER

Comment Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules and engages diverse ligands relevant to distinct pathological processes. One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products, which occur in diabetes, at sites of oxidant stress in tissues, and in renal failure and amyloidoses.
Formal Description
Interaction-ID: 16844

drug/chemical compound

Advanced glycation end-product

interacts (colocalizes) with

gene/protein

AGER

Comment One pathway of RAGE-dependent cellular perturbation includes activation of p21ras, followed by activation of mitogen-activated protein (MAP) kinases and nuclear translocation of the transcription factor NF-kappaB, resulting in transcription of target genes.
Formal Description
Interaction-ID: 16845

gene/protein

AGER

increases_activity of

gene/protein

HRAS

Drugbank entries Show/Hide entries for HRAS
Comment One pathway of RAGE-dependent cellular perturbation includes activation of p21ras, followed by activation of mitogen-activated protein (MAP) kinases and nuclear translocation of the transcription factor NF-kappaB, resulting in transcription of target genes.
Formal Description
Interaction-ID: 16846

gene/protein

AGER

increases_activity of

gene/protein

MAPK

Comment One pathway of RAGE-dependent cellular perturbation includes activation of p21ras, followed by activation of mitogen-activated protein (MAP) kinases and nuclear translocation of the transcription factor NF-kappaB, resulting in transcription of target genes.
Formal Description
Interaction-ID: 16847

gene/protein

AGER

increases_transport of

complex/PPI

NF-kappaB complex

into the nucleus
Comment One pathway of RAGE-dependent cellular perturbation includes activation of p21ras, followed by activation of mitogen-activated protein (MAP) kinases and nuclear translocation of the transcription factor NF-kappaB, resulting in transcription of target genes.
Formal Description
Interaction-ID: 16848

gene/protein

AGER

increases_activity of

complex/PPI

NF-kappaB complex

Comment Expression of NF-kappaB-regulated genes is observed in pathological samples in which RAGE and its ligands are present at high levels. For example, increased expression of VCAM-1 and heme oxygenase type I have been noted in diabetic tissues. Infusion of AGEs into rodents enhances expression of these cell stress markers in a RAGE-dependent manner and is closely correlated with NF-kappaB activation.
Formal Description
Interaction-ID: 16849

complex/PPI

NF-kappaB complex

increases_expression of

gene/protein

VCAM1

Drugbank entries Show/Hide entries for VCAM1
Comment Expression of NF-kappaB-regulated genes is observed in pathological samples in which RAGE and its ligands are present at high levels. For example, increased expression of VCAM-1 and heme oxygenase type I have been noted in diabetic tissues. Infusion of AGEs into rodents enhances expression of these cell stress markers in a RAGE-dependent manner and is closely correlated with NF-kappaB activation.
Formal Description
Interaction-ID: 16850

complex/PPI

NF-kappaB complex

increases_expression of

gene/protein

HMOX1

Drugbank entries Show/Hide entries for HMOX1
Comment Increased expression of VCAM-1 in diabetic vasculature would enhance mononuclear phagocyte adherence to the vessel wall promoting atherogenesis.
Formal Description
Interaction-ID: 16851

gene/protein

VCAM1

increases_activity of

Drugbank entries Show/Hide entries for VCAM1
Comment Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules and engages diverse ligands relevant to distinct pathological processes. One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products, which occur in diabetes, at sites of oxidant stress in tissues, and in renal failure and amyloidoses.
Formal Description
Interaction-ID: 16852

increases_quantity of

drug/chemical compound

Advanced glycation end-product