RGD Reference Report - p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression: roscovitine augments p21 levels. - Rat Genome Database

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p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression: roscovitine augments p21 levels.

Authors: Park, JY  Schutzer, WE  Lindsley, JN  Bagby, SP  Oyama, TT  Anderson, S  Weiss, RH 
Citation: Park JY, etal., BMC Nephrol. 2007 Aug 22;8:12.
RGD ID: 2289666
Pubmed: PMID:17714589   (View Abstract at PubMed)
PMCID: PMC2045080   (View Article at PubMed Central)
DOI: DOI:10.1186/1471-2369-8-12   (Journal Full-text)

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease with few treatment options other than renal replacement therapy. p21, a cyclin kinase inhibitor which has pleiotropic effects on the cell cycle, in many cases acts to suppress cell cycle progression and to prevent apoptosis. Because defects in cell cycle arrest and apoptosis of renal tubular epithelial cells occur in PKD, and in light of earlier reports that polycystin-1 upregulates p21 and that the cyclin-dependent kinase inhibitor roscovitine arrests progression in a mouse model, we asked whether (1) p21 deficiency might underlie ADPKD and (2) the mechanism of the salutary roscovitine effect on PKD involves p21. METHODS: p21 levels in human and animal tissue samples as well as cell lines were examined by immunoblotting and/or immunohistochemisty. Apoptosis was assessed by PARP cleavage. p21 expression was attenuated in a renal tubular epithelial cell line by antisense methods, and proliferation in response to p21 attenuation and to roscovitine was assessed by the MTT assay. RESULTS: We show that p21 is decreased in human as well as a non-transgenic rat model of ADPKD. In addition, hepatocyte growth factor, which induces transition from a cystic to a tubular phenotype, increases p21 levels. Furthermore, attenuation of p21 results in augmentation of cell cycle transit in vitro. Thus, levels of p21 are inversely correlated with renal tubular epithelial cell proliferation. Roscovitine, which has been shown to arrest progression in a murine model of PKD, increases p21 levels and decreases renal tubular epithelial cell proliferation, with no affect on apoptosis. CONCLUSION: The novelty of our study is the demonstration in vivo in humans and rat models of a decrement of p21 in cystic kidneys as compared to non-cystic kidneys. Validation of a potential pathogenetic model of increased cyst formation due to enhanced epithelial proliferation and apoptosis mediated by p21 suggests a mechanism for the salutary effect of roscovitine in ADPKD and supports further investigation of p21 as a target for future therapy.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
autosomal dominant polycystic kidney disease  IEP 2289666; 2289666protein:decreased expression:kidneyRGD 
autosomal dominant polycystic kidney disease  ISOCdkn1a (Rattus norvegicus) and CDKN1A (Homo sapiens)2289666protein:decreased expression:kidneyRGD 

Objects Annotated

Genes (Rattus norvegicus)
Cdkn1a  (cyclin-dependent kinase inhibitor 1A)

Genes (Mus musculus)
Cdkn1a  (cyclin dependent kinase inhibitor 1A)

Genes (Homo sapiens)
CDKN1A  (cyclin dependent kinase inhibitor 1A)


Additional Information