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(American Journal of Pathology. 2001;158:1091-1100.)
© 2001 American Society for Investigative Pathology

Regular Articles

High Glucose-Induced Hypertrophy of Mesangial Cells Requires p27Kip1, an Inhibitor of Cyclin-Dependent Kinases

Gunter Wolf*, Regine Schroeder*, Gunther Zahner*, Rolf A. K. Stahl* and Stuart J. Shankland{dagger}

From the Department of Medicine,*
Division of Nephrology and Osteology, University of Hamburg, Hamburg, Germany; and the Department of Medicine,{dagger}
Division of Nephrology, University of Washington School of Medicine, Seattle, Washington

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 p21Cip and p27Kip1. 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 p21Cip1 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)-ß mRNA and protein expression, DNA synthesis and cell cycle progression were increased by high glucose in p27Kip1-/- cells. Exogenous TGF-ß comparably induced fibronectin mRNA in p27Kip1+/+ and -/- cells suggesting intact TGF-ß 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.




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