Differential expression of cyclin-dependent kinase inhibitors in human glomerular disease: role in podocyte proliferation and maturation.
BACKGROUND
Normal human podocytes are terminally differentiated and quiescent cells. It is not known why podocytes fail to proliferate in response to most forms of injury. Proliferation is regulated by cell cycle proteins and their inhibitors. The Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors (p21, p27, p57) in general prevent proliferation by inhibiting cyclin-CDK complexes. In the current study, we determined the expression and possible role of specific CDK inhibitors in podocyte proliferation in human disease characterized by podocyte injury.


METHODS
Immunostaining was performed for the CDK inhibitors p21, p27, and p57 and the proliferation marker Ki-67 on renal biopsies from patients with minimal change disease (MCD; N = 6), membranous glomerulopathy (MGN; N = 19), cellular variant of focal segmental glomerulosclerosis (FSGS; N = 12), collapsing glomerulopathy (CG; N = 9), and HIV-associated nephropathy (HIVAN; N = 16). Adult nephrectomy specimens without evidence of glomerular disease served as controls (N = 9).


RESULTS
Normal quiescent podocytes express p27 and p57, but not p21. In diseases without podocyte proliferation (MCD, MGN), p21, p27, and p57 expression did not change. In contrast, there was a uniform decrease in p27 and p57 immunostaining in diseases with podocyte proliferation (cellular FSGS, CG, and HIVAN). This was accompanied by the de novo expression of p21 in podocytes.


CONCLUSIONS
Our results show that podocyte quiescence may require the presence of the CDK inhibitors p27 and p57. In human glomerular diseases, a decrease in p27 and p57 may be permissive for the altered proliferative podocyte phenotype. p21 may have a multifactorial role in podocyte cell cycle regulation.
Department of Medicine, Division of Nephrology, University of Washington School of Medicine, Seattle 98195-6521, USA. stuarts@u.washington.edu
S J
SJ
Shankland
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Eitner
K L
KL
Hudkins
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T
Goodpaster
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D'Agati
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Alpers
D016263:AIDS-Associated Nephropathy / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000906:Antibodies; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology; D015433:Glomerulonephritis, Membranous / Q000378:metabolism* / Q000473:pathology*; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D019394:Ki-67 Antigen / Q000032:analysis; D007678:Kidney Glomerulus / Q000737:chemistry / Q000201:enzymology* / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology; D009687:Nuclear Proteins / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology; D025521:Tumor Suppressor Proteins
D000906:Antibodies; C493956:CDKN1A protein, human; C493964:CDKN1C protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050761:Cyclin-Dependent Kinase Inhibitor p57; D016213:Cyclins; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases