CIDeRplusGeneral Information:
| Id: | 8,191 |
| Diseases: |
Diabetes mellitus, type II
- [OMIM]
Insulin resistance Nephropathy, diabetic |
| Mammalia | |
| review | |
| Reference: | Vukovic I et al.(2015) The missing link - likely pathogenetic role of GM3 and other gangliosides in the development of diabetic nephropathy Kidney Blood Press. Res. 40: 306-314 [PMID: 26043887] |
Interaction Information:
| Comment | Diabetes mellitus is a major cause of end-stage renal disease (ESRD) worldwide, in both first-world countries and in developing ones. It occurs in up to 40% of diabetic patients, somewhat more frequently in type I than in type II. |
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Formal Description Interaction-ID: 82295 |
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| Comment | Diabetes mellitus is a major cause of end-stage renal disease (ESRD) worldwide, in both first-world countries and in developing ones. It occurs in up to 40% of diabetic patients, somewhat more frequently in type I than in type II. |
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Formal Description Interaction-ID: 82490 |
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| Comment | Diabetic nephropathy is characterized by an onset of microalbuminuria coupled with increased glomerular filtration rate (GFR) in the initial stage, followed by progressive increase of the total urine protein excretion and decrease of the GFR. A fully developed nephrotic syndrome is marked by total urine protein excretion of over 3.5 g/day. |
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Formal Description Interaction-ID: 82491 |
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| Comment | Diabetic nephropathy is characterized by an onset of microalbuminuria coupled with increased glomerular filtration rate (GFR) in the initial stage, followed by progressive increase of the total urine protein excretion and decrease of the GFR. A fully developed nephrotic syndrome is marked by total urine protein excretion of over 3.5 g/day. |
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Formal Description Interaction-ID: 82492 |
disease Nephropathy, diabetic increases_activity of |
| Comment | Diabetes mellitus is a major cause of end-stage renal disease (ESRD) worldwide, in both first-world countries and in developing ones. It occurs in up to 40% of diabetic patients, somewhat more frequently in type I than in type II. |
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Formal Description Interaction-ID: 82493 |
disease Nephropathy, diabetic increases_activity of disease End-stage renal disease |
| Comment | The proliferation of the extracellular matrix plays a key role in the pathogenesis of diabetic nephropathy. |
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Formal Description Interaction-ID: 82495 |
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| Comment | The expansion of extracellular matrix causes thickening of glomerular basal membrane, as well as the tubulo-interstitial and mesangial compartment. This mechanism is responsible for obstruction of the glomerular filtration. |
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Formal Description Interaction-ID: 82500 |
process increases_activity of |
| Comment | Inflammatory pathways seem to be interlinked with those of systemic and local hypertensive pathomechanisms, since angiotensin II, through the AT1 receptor, induces the protein kinase C (PKC) activity, and also rises the intracellular levels of reactive oxygen species (ROS), contributing to the inflammatory process. |
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Formal Description Interaction-ID: 82501 |
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| Drugbank entries | Show/Hide entries for AGTR1 |
| Comment | Inflammatory pathways seem to be interlinked with those of systemic and local hypertensive pathomechanisms, since angiotensin II, through the AT1 receptor, induces the protein kinase C (PKC) activity, and also rises the intracellular levels of reactive oxygen species (ROS), contributing to the inflammatory process. |
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Formal Description Interaction-ID: 82503 |
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| Drugbank entries | Show/Hide entries for AGTR1 |
| Comment | Inflammatory pathways seem to be interlinked with those of systemic and local hypertensive pathomechanisms, since angiotensin II, through the AT1 receptor, induces the protein kinase C (PKC) activity, and also rises the intracellular levels of reactive oxygen species (ROS), contributing to the inflammatory process. |
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Formal Description Interaction-ID: 82504 |
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| Comment | Activation of Gq alpha subunit-coupled signaling pathways in glomerular podocytes promotes renal injury. |
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Formal Description Interaction-ID: 82507 |
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| Comment | The AT1 receptor is a G protein-coupled receptor. Commonly, Gq alpha subunit of G protein-coupled receptors activates phospholipase C. Phospholipase C generates DAG as second messenger of AT1 receptor binding, further activating protein kinase C. PKC induction by AT1 is synergistically affected by reactive oxygen species, generated by interactions of AGE and corresponding receptors, which also increases the phospholipase C activity producing more molecular units of DAG. This double pathway PKC activation defines its central role in diabetic nephropathy pathogenesis. |
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Formal Description Interaction-ID: 82511 |
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| Drugbank entries | Show/Hide entries for PLC |
| Comment | The AT1 receptor is a G protein-coupled receptor. Commonly, Gq alpha subunit of G protein-coupled receptors activates phospholipase C. Phospholipase C generates DAG as second messenger of AT1 receptor binding, further activating protein kinase C. PKC induction by AT1 is synergistically affected by reactive oxygen species, generated by interactions of AGE and corresponding receptors, which also increases the phospholipase C activity producing more molecular units of DAG. This double pathway PKC activation defines its central role in diabetic nephropathy pathogenesis. |
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Formal Description Interaction-ID: 82515 |
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| Drugbank entries | Show/Hide entries for PLC |
| Comment | The AT1 receptor is a G protein-coupled receptor. Commonly, Gq alpha subunit of G protein-coupled receptors activates phospholipase C. Phospholipase C generates DAG as second messenger of AT1 receptor binding, further activating protein kinase C. PKC induction by AT1 is synergistically affected by reactive oxygen species, generated by interactions of AGE and corresponding receptors, which also increases the phospholipase C activity producing more molecular units of DAG. This double pathway PKC activation defines its central role in diabetic nephropathy pathogenesis. |
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Formal Description Interaction-ID: 82516 |
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| Comment | The AT1 receptor is a G protein-coupled receptor. Commonly, Gq alpha subunit of G protein-coupled receptors activates phospholipase C. Phospholipase C generates DAG as second messenger of AT1 receptor binding, further activating protein kinase C. PKC induction by AT1 is synergistically affected by reactive oxygen species, generated by interactions of AGE and corresponding receptors, which also increases the phospholipase C activity producing more molecular units of DAG. This double pathway PKC activation defines its central role in diabetic nephropathy pathogenesis. |
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Formal Description Interaction-ID: 82517 |
gene/protein Protein kinase C increases_activity of disease Nephropathy, diabetic |
| Comment | PKC is responsible for up regulation of NADPH-oxidase expression, additionally increasing ROS quantities and the intensity of the inflammatory process and for induction of the cytokine TGF-beta. |
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Formal Description Interaction-ID: 82518 |
gene/protein Protein kinase C increases_activity of complex/PPI NADPH oxidase complex |
| Comment | PKC is responsible for up regulation of NADPH-oxidase expression, additionally increasing ROS quantities and the intensity of the inflammatory process and for induction of the cytokine TGF-beta. |
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Formal Description Interaction-ID: 82519 |
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| Drugbank entries | Show/Hide entries for TGFB1 |
| Comment | Gangliosides are categorized according to the Svennerholm classification. Letters ‚ÄúM, D, T, Q‚ÄĚ and ‚ÄúP‚ÄĚ indicate the number of sialic acid groups on molecules (M=1...P=5). Numbers ‚Äú1-4‚ÄĚ designate the number of carbohydrate groups bound to ceramide, derived from the formula; n = 5 - number of carbohydrate groups. When present, lowercase letters ‚Äúa‚ÄĚ, ‚Äúb‚ÄĚ and ‚Äúc‚ÄĚ indicate the number of sialic acids on the inner galactose segment. Therefore, the eponymous GM3 ganglioside contains a single sialic group with 2 carbohydrate groups bound to a ceramide structure. GM3 formation is catalyzed by the GM3 synthase, a lactosylceramide alpha 2,3 ‚Äď sialyl transferase, that catalyses the N-acetylneuraminic (sialic) acid transfer on the terminal galactose residue of lactosylceramide. Glycosyltransferases are enzymes that catalyse ganglioside synthesis and determine the key sequence of carbohydrates in the glycosphingolipid chain. |
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Formal Description Interaction-ID: 82520 |
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| Comment | GM3 ganglioside is linked with a variety of physiological functions on the molecular level, such as: control of cell proliferation and differentiation, apoptosis, cellular signaling pathways, cell adhesion and mobility. |
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Formal Description Interaction-ID: 82524 |
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| Comment | GM3 ganglioside is linked with a variety of physiological functions on the molecular level, such as: control of cell proliferation and differentiation, apoptosis, cellular signaling pathways, cell adhesion and mobility. |
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Formal Description Interaction-ID: 82525 |
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| Comment | GM3 ganglioside is linked with a variety of physiological functions on the molecular level, such as: control of cell proliferation and differentiation, apoptosis, cellular signaling pathways, cell adhesion and mobility. |
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Formal Description Interaction-ID: 82526 |
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| Comment | GM3 ganglioside is linked with a variety of physiological functions on the molecular level, such as: control of cell proliferation and differentiation, apoptosis, cellular signaling pathways, cell adhesion and mobility. |
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Formal Description Interaction-ID: 82527 |
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| Comment | A significant body of evidence emphasizes negative modulation effects of GM3 on insulin-mediated signaling pathways, at the same time highlighting its potential role in the development of type II diabetes. |
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Formal Description Interaction-ID: 82530 |
drug/chemical compound decreases_activity of |
| Comment | A significant body of evidence emphasizes negative modulation effects of GM3 on insulin-mediated signaling pathways, at the same time highlighting its potential role in the development of type II diabetes. |
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Formal Description Interaction-ID: 82531 |
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| Comment | Another important nephrologic clinical syndrome has been linked with GM3 as an underlying cause, namely the polycystic kidney disease (PKD) and more notably the nephronophthisis related-PKD. |
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Formal Description Interaction-ID: 82532 |
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| Comment | GM3 and the GM3 precursor, glucosylceramide (GlcCer), seem to promote cystogenic activity. |
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Formal Description Interaction-ID: 82533 |
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| Comment | GM3 and the GM3 precursor, glucosylceramide (GlcCer), seem to promote cystogenic activity. |
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Formal Description Interaction-ID: 82534 |
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| Comment | Loss of the GM3 synthase gene was reported to have a protective effect on forming cystic structures in rats, while other studies highlighted the inhibitory effects of GM3 on cell cycle induction and Akt/mTOR signaling pathway, a pathway linked with cystogenic effects. |
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Formal Description Interaction-ID: 82535 |
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| Comment | Advanced glycation products (AGE) are a key biochemical characteristic of diabetes. In a concentration-dependent reaction, surplus sugar molecules bind to protein structures without the mediation of enzymes, causing conformational changes and protein function disruptions. |
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Formal Description Interaction-ID: 82537 |
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| Comment | A positive correlation between the increase in AGE levels and increased levels of a-series gangliosides was found in rat renal mesangial cells, with GM3, GM2 and GM1 particularly increased. |
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Formal Description Interaction-ID: 82538 |
drug/chemical compound Advanced glycation end-product increases_quantity of drug/chemical compound |
| Comment | A positive correlation between the increase in AGE levels and increased levels of a-series gangliosides was found in rat renal mesangial cells, with GM3, GM2 and GM1 particularly increased. |
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Formal Description Interaction-ID: 82539 |
drug/chemical compound Advanced glycation end-product increases_quantity of drug/chemical compound |
| Comment | A positive correlation between the increase in AGE levels and increased levels of a-series gangliosides was found in rat renal mesangial cells, with GM3, GM2 and GM1 particularly increased. |
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Formal Description Interaction-ID: 82540 |
drug/chemical compound Advanced glycation end-product increases_quantity of drug/chemical compound |
| Comment | GM3 is the most abundant renal ganglioside and together with ganglioside GM1 constitutes lipid rafts. GM3 rafts are localized predominantly on the peaks of microvillus-like protrusions in the apical membrane of canine kidney cells, whereas GM1rafts are distributed mainly on the slops of protrusions or the valleys between protrusions in the plasma membranes. |
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Formal Description Interaction-ID: 82541 |
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| Comment | GM3 is the most abundant renal ganglioside and together with ganglioside GM1 constitutes lipid rafts. GM3 rafts are localized predominantly on the peaks of microvillus-like protrusions in the apical membrane of canine kidney cells, whereas GM1rafts are distributed mainly on the slops of protrusions or the valleys between protrusions in the plasma membranes. |
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Formal Description Interaction-ID: 82542 |
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| Comment | Loss of the GM3 synthase gene was reported to have a protective effect on forming cystic structures in rats, while other studies highlighted the inhibitory effects of GM3 on cell cycle induction and Akt/mTOR signaling pathway, a pathway linked with cystogenic effects. |
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Formal Description Interaction-ID: 82544 |
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