title: Cyclin kinase inhibitors are increased during experimental membranous nephropathy: potential role in limiting glomerular epithelial cell proliferation in vivo.
abstract: The inadequate proliferative response of the visceral glomerular epithelial cell (GEC) following injury in vivo may contribute to the development of progressive glomerulosclerosis in many forms of glomerular disease. Cell proliferation is ultimately controlled by cell-cycle regulatory proteins, including cyclins that bind to cyclin dependent kinases (CDK), and the active complex formed is necessary for progression through the cell-cycle. By inhibiting cyclin-CDK complexes, cyclin kinase inhibitors arrest the cell-cycle and prevent proliferation. To determine the mechanisms that may be responsible for the lack of GEC proliferation in vivo, we examined GEC expression of specific cell-cycle proteins in normal rats and in the passive Heymann nephritis (PHN) model of membranous nephropathy, where the GEC are the target of complement-mediated injury. Following antibody deposition and complement activation there was a marked up-regulation in the cyclin kinase inhibitors p21 and p27 in rats with PHN. By associating with cyclin A-CDK2 complexes, p21 and p27 limited the kinase activity of CDK2. Giving bFGF to rats with PHN was associated with an increase in GEC mitosis and ploidy and a decrease in expression of p21, but not CDK2 or p27. Furthermore, apoptosis was not present in PHN, but was increased in rats given bFGF. In conclusion, this study shows that the low proliferative capacity of the GEC in vivo in response to immune injury may be due to an increase in the expression of specific cyclin kinase inhibitors. The increase in mitosis in PHN rats given bFGF may be due to a decrease in p21. Thus, changes in cell cycle regulatory proteins may regulate the response of GEC to injury and underlie the development of progressive glomerulosclerosis in diseases of the GEC.
authors.affiliation: Department of Nephrology, University of Washington, Seattle, USA. stuartjs@u.washington.edu
authors.forename: S J
authors.initials: SJ
authors.lastname: Shankland
authors.forename: J
authors.initials: J
authors.lastname: Floege
authors.forename: S E
authors.initials: SE
authors.lastname: Thomas
authors.forename: M
authors.initials: M
authors.lastname: Nangaku
authors.forename: C
authors.initials: C
authors.lastname: Hugo
authors.forename: J
authors.initials: J
authors.lastname: Pippin
authors.forename: K
authors.initials: K
authors.lastname: Henne
authors.forename: D M
authors.initials: DM
authors.lastname: Hockenberry
authors.forename: R J
authors.initials: RJ
authors.lastname: Johnson
authors.forename: W G
authors.initials: WG
authors.lastname: Couser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001710:Biotin; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D053938:DNA Fragmentation; D003856:Deoxyuracil Nucleotides; D004791:Enzyme Inhibitors / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D016193:G1 Phase / Q000502:physiology; D015433:Glomerulonephritis, Membranous / Q000201:enzymology*; D007678:Kidney Glomerulus / Q000166:cytology* / Q000201:enzymology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016196:S Phase / Q000502:physiology; D013194:Staining and Labeling; D025521:Tumor Suppressor Proteins
chemical_list: C493958:Cdkn1a protein, rat; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003856:Deoxyuracil Nucleotides; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D016222:Fibroblast Growth Factor 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D001710:Biotin; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases