p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression

Roscovitine augments p21 levels

Jin Young Park, William E. Schutzer, Jessie N. Lindsley, Susan Bagby, Terry T. Oyama, Sharon Anderson, Robert H. Weiss

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number12
JournalBMC Nephrology
Volume8
DOIs
StatePublished - 2007

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Autosomal Dominant Polycystic Kidney
Polycystic Kidney Diseases
Cell Cycle
Epithelial Cells
Apoptosis
Kidney
Cyclin-Dependent Kinase Inhibitor p21
Cell Proliferation
Cystic Kidney Diseases
Cell Line
Inborn Genetic Diseases
Renal Replacement Therapy
Hepatocyte Growth Factor
Cell Cycle Checkpoints
Immunoblotting
Cysts
Up-Regulation
roscovitine
Phenotype
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression : Roscovitine augments p21 levels. / Park, Jin Young; Schutzer, William E.; Lindsley, Jessie N.; Bagby, Susan; Oyama, Terry T.; Anderson, Sharon; Weiss, Robert H.

In: BMC Nephrology, Vol. 8, 12, 2007.

Research output: Contribution to journalArticle

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abstract = "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.",
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AU - Bagby, Susan

AU - Oyama, Terry T.

AU - Anderson, Sharon

AU - Weiss, Robert H.

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