Document Detail

High glucose-induced hypertrophy of mesangial cells requires p27(Kip1), an inhibitor of cyclin-dependent kinases.
MedLine Citation:
PMID:  11238057     Owner:  NLM     Status:  MEDLINE    
Hypertrophy of mesangial cells is one of the earliest morphological alterations in the kidney after the onset of diabetes mellitus. We have previously shown that cultured mesangial cells exposed to high ambient glucose arrest in the G1 phase of the cell cycle and that this is associated with an increased expression of inhibitors of the cyclin-dependent kinase (CDK)-inhibitors p21(Cip) and p27(Kip1). To further investigate a potential role of p27Kip1 in the development of glucose-induced hypertrophy, mesangial cells from p27Kip1 wild-type (+/+) and knockout (-/-) mice were established. High glucose medium (450 mg/dl) increased p21(Cip1) protein in p27Kip1+/+ and -/- mesangial cells, and increased p27Kip1 protein levels in p27Kip1+/+ cells. In contrast to high glucose increasing de novo protein synthesis in p27Kip1+/+ cells, high glucose did not increase protein synthesis in p27Kip1-/- cells. High glucose also reduced DNA synthesis and caused cell cycle arrest in p27Kip1+/+ cells. In contrast, despite an increase in transforming growth factor (TGF)-beta mRNA and protein expression, DNA synthesis and cell cycle progression were increased by high glucose in p27Kip1-/- cells. Exogenous TGF-beta comparably induced fibronectin mRNA in p27Kip1+/+ and -/- cells suggesting intact TGF-beta receptor transduction. In addition, high glucose failed to increase the total protein/cell number ratio in p27Kip1-/- cells. However, in the presence of high glucose, reconstituting p27Kip1 expression by transient or stable transfection in p27Kip1-/- cells, using an inducible expression system, increased the de novo protein synthesis and restored G1-phase arrest. These results show that p27Kip1 is required for glucose-induced mesangial cell hypertrophy and cell cycle arrest.
G Wolf; R Schroeder; G Zahner; R A Stahl; S J Shankland
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The American journal of pathology     Volume:  158     ISSN:  0002-9440     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2001 Mar 
Date Detail:
Created Date:  2001-03-12     Completed Date:  2001-04-05     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1091-100     Citation Subset:  AIM; IM    
University of Hamburg, University Hospital Eppendorf, Department of Medicine, Division of Nephrology and Osteology, Pavilion 61, Martinistrasse 52, D-20246 Hamburg, Germany.
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MeSH Terms
Cell Cycle Proteins*
Cell Division
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases / antagonists & inhibitors*
Cyclins / biosynthesis
Gene Expression Regulation
Hypertrophy / etiology*,  metabolism,  pathology
Kidney / cytology*,  metabolism,  pathology
Mice, Knockout
Microtubule-Associated Proteins / biosynthesis,  genetics,  physiology*
Models, Biological
Transforming Growth Factor beta / biosynthesis
Tumor Suppressor Proteins*
Grant Support
Reg. No./Substance:
0/Cdkn1a protein, mouse; 0/Cdkn1b protein, mouse; 0/Cell Cycle Proteins; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Microtubule-Associated Proteins; 0/Transforming Growth Factor beta; 0/Tumor Suppressor Proteins; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 50-99-7/Glucose; EC Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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