Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2002-6-12
pubmed:abstractText
Inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, also known as statins, are lipid-lowering agents widely used in the prevention of coronary heart disease. Recent experimental and clinical data, however, indicate that the overall benefits of statin therapy may exceed its cholesterol-lowering properties. We postulate that statins may ameliorate the detrimental effects of high glucose (HG)-induced proliferation of mesangial cells (MCs), a feature of early stages of diabetic nephropathy, by preventing Rho isoprenylation. Rat MCs cultured in HG milieu were treated with and without simvastatin, an HMG-CoA reductase inhibitor. Simvastatin inhibited HG-induced MC proliferation as measured by [(3)H]thymidine incorporation. This inhibitory effect was reversed with geranylgeranyl pyrophosphate, an isoprenoid intermediate of the cholesterol biosynthetic pathway. At the cell-cycle level, the HG-induced proliferation of MCs was associated with a decrease in cyclin dependent kinase (CDK) inhibitor p21 protein expression accompanied by an increase in CDK4 and CDK2 kinase activities. Simvastatin reversed the down-regulation of p21 protein expression and decreased CDK4 and CDK2 kinase activities. Exposure of MCs to HG was associated with an increase in membrane-associated Ras and Rho GTPase protein expression. Cotreatment of MCs with simvastatin reversed HG-induced Ras and Rho membrane translocation. Immunofluorescence microscopy revealed that the overexpression of the dominant-negative RhoA led to a significant increase in p21 expression. Our data suggest that simvastatin represses the HG-induced Rho GTPase/p21 signaling in glomerular MCs. Thus, this study provides a molecular basis for the use of statins, independently of their cholesterol-lowering effect, in early stages of diabetic nephropathy.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-10203357, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-10419514, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-10500210, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-10504475, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-10637210, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-10835338, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-10946302, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-11164838, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-11249858, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-11260395, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-11260396, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-11485822, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-11557735, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-11715015, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-11715034, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-11742412, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-11742414, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-1357223, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-1643658, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-1967820, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-2294729, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-3367557, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-3933003, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-7489845, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-7536630, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-7566157, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-7716512, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-7752595, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-7758941, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-7954821, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-8231022, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-9308960, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-9405913, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-9553123, http://linkedlifedata.com/resource/pubmed/commentcorrection/12048257-9685162
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0027-8424
pubmed:author
pubmed:issnType
Print
pubmed:day
11
pubmed:volume
99
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
8301-5
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:12048257-Animals, pubmed-meshheading:12048257-Glucose, pubmed-meshheading:12048257-Rats, pubmed-meshheading:12048257-Diabetic Nephropathies, pubmed-meshheading:12048257-Enzyme Inhibitors, pubmed-meshheading:12048257-Cell Membrane, pubmed-meshheading:12048257-Cells, Cultured, pubmed-meshheading:12048257-Cell Differentiation, pubmed-meshheading:12048257-Models, Biological, pubmed-meshheading:12048257-DNA Replication, pubmed-meshheading:12048257-Protein Transport, pubmed-meshheading:12048257-Signal Transduction, pubmed-meshheading:12048257-Glomerular Mesangium, pubmed-meshheading:12048257-Hydroxymethylglutaryl-CoA Reductase Inhibitors, pubmed-meshheading:12048257-Transfection, pubmed-meshheading:12048257-Simvastatin, pubmed-meshheading:12048257-Cyclins, pubmed-meshheading:12048257-rho GTP-Binding Proteins
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