Activation of cyclin D1-Cdk4 and Cdk4-directed phosphorylation of RB protein in diabetic mesangial hypertrophy.
To determine the role of cell-cycle proteins in regulating pathological renal hypertrophy, diabetes was induced in mice expressing a human retinoblastoma (RB) transgene and in wild-type littermates. Whole-kidney and glomerular hypertrophy caused by hyperglycemia was associated with specific G1 phase cell-cycle events: early and sustained increase in expression of cyclin D1 and activation of cyclin D1-cdk4 complexes, but no change in expression of cyclin E or cdk2 activity. Overexpression of RB alone likewise caused hypertrophy and increased only cyclin D1-cdk4 activity; these effects were not further augmented by high glucose. Identical observations were made when isolated mesangial cells conditionally overexpressing RB from a tetracycline-repressible system hypertrophied in response to high glucose. A mitogenic signal in the same cell-culture system, in contrast, transiently and sequentially activated both cyclin D1-cdk4 and cyclin E-cdk2. In vivo and in cultured mesangial cells, high glucose resulted in persistent partial phosphorylation of RB, an event catalyzed specifically by cyclin D1-cdk4. These data indicate that mesangial hypertrophy caused by hyperglycemia in diabetes results in sustained cyclin D1-cdk4-dependent phosphorylation of RB and maintenance of mesangial cells in the early-to-middle G1 phase of the cell cycle.
Féliers
Denis
D
Department of Medicine, Division of Nephrology, South Texas Veterans Health Care System, San Antonio, Texas, USA.
Frank
Meredith A
MA
Riley
Daniel J
DJ
D000818:Animals; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006984:Hypertrophy; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D019938:Cyclin D1; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases