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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2009-8-20
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pubmed:abstractText |
Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We have recently shown that epidermal growth factor receptor (EGFR) transactivation mediates high glucose (HG)-induced collagen I upregulation through PI3K-PKCbeta1-Akt signaling in mesangial cells (MC). Phospholipase Cgamma1 (PLCgamma1) interacts with activated growth factor receptors and activates classic PKC isoforms. We thus studied its role in HG-induced collagen I upregulation in MC. Primary rat MC were treated with HG (30 mM) or mannitol as osmotic control. Protein kinase activation was assessed by Western blotting and collagen I upregulation by Northern blotting. Diabetes was induced in rats by streptozotocin. HG treatment for 1 h led to PLCgamma1 membrane translocation and Y783 phosphorylation, both indicative of its activation. Mannitol was without effect. PLCgamma1 Y783 phosphorylation was also seen in cortex and glomeruli of diabetic rats. HG induced a physical association between EGFR and PLCgamma1 as identified by coimmunoprecipitation. PLCgamma1 activation required EGFR kinase activity since it was prevented by the EGFR inhibitor AG1478 or overexpression of kinase-inactive EGFR (K721A). Phosphoinositide-3-OH kinase inhibition also prevented PLCgamma1 activation. HG-induced Akt S473 phosphorylation, effected by PKCbeta1, was inhibited by the PLCgamma inhibitor U73122. PLCgamma1 inhibition or downregulation by small interference RNA also prevented HG-induced collagen I upregulation. Our results indicate that EGFR-PLCgamma1 signaling mediates HG-induced PKCbeta1-Akt activation and subsequent collagen I upregulation in MC. Inhibition of EGFR or PLCgamma1 may provide attractive therapeutic targets for the treatment of diabetic nephropathy.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/1-(6-((3-methoxyestra-1,3,5(10)-trie...,
http://linkedlifedata.com/resource/pubmed/chemical/Blood Glucose,
http://linkedlifedata.com/resource/pubmed/chemical/Collagen Type I,
http://linkedlifedata.com/resource/pubmed/chemical/Egfr protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Estrenes,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phospholipase C gamma,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase C,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrrolidinones,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Epidermal Growth Factor,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrphostins,
http://linkedlifedata.com/resource/pubmed/chemical/protein kinase C beta,
http://linkedlifedata.com/resource/pubmed/chemical/tyrphostin AG 1478
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
1522-1466
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
297
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
F822-34
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pubmed:dateRevised |
2011-4-28
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pubmed:meshHeading |
pubmed-meshheading:19605547-Animals,
pubmed-meshheading:19605547-Blood Glucose,
pubmed-meshheading:19605547-Cells, Cultured,
pubmed-meshheading:19605547-Collagen Type I,
pubmed-meshheading:19605547-Diabetes Mellitus, Experimental,
pubmed-meshheading:19605547-Diabetic Nephropathies,
pubmed-meshheading:19605547-Enzyme Activation,
pubmed-meshheading:19605547-Enzyme Inhibitors,
pubmed-meshheading:19605547-Estrenes,
pubmed-meshheading:19605547-Female,
pubmed-meshheading:19605547-Male,
pubmed-meshheading:19605547-Mesangial Cells,
pubmed-meshheading:19605547-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:19605547-Phospholipase C gamma,
pubmed-meshheading:19605547-Phosphorylation,
pubmed-meshheading:19605547-Protein Kinase C,
pubmed-meshheading:19605547-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:19605547-Pyrrolidinones,
pubmed-meshheading:19605547-RNA Interference,
pubmed-meshheading:19605547-Rats,
pubmed-meshheading:19605547-Rats, Sprague-Dawley,
pubmed-meshheading:19605547-Receptor, Epidermal Growth Factor,
pubmed-meshheading:19605547-Tyrphostins,
pubmed-meshheading:19605547-Up-Regulation
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pubmed:year |
2009
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pubmed:articleTitle |
EGFR-PLCgamma1 signaling mediates high glucose-induced PKCbeta1-Akt activation and collagen I upregulation in mesangial cells.
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pubmed:affiliation |
Division of Nephrology, McMaster University, Hamilton, Ontario, Canada.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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