Disparate effects of roscovitine on renal tubular epithelial cell apoptosis and senescence: Implications for autosomal dominant polycystic kidney disease

Jin Young Park, See Hyoung Park, Robert H Weiss

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background/Aims: Control of apoptosis in autosomal dominant polycystic kidney disease (ADPKD) and in at least some cancers is likely regulated by the endogenous cyclin kinase inhibitor p21, levels of this protein being decreased in ADPKD and increased in many malignancies. The cyclin kinase inhibitor roscovitine has shown efficacy in treatment of murine PKD. We asked how a single agent can be efficacious in both PKD and cancer. Methods: Renal tubular epithelial cells were incubated at diverse roscovitine concentrations; apoptosis and senescence were measured. Subsequently, levels of pro- and antiapoptotic proteins were evaluated. Results: Renal tubular epithelial cells exposed to 'low' concentrations of roscovitine showed minimal apoptosis in association with markedly increased levels of the antiapoptotic protein p21, and these cells became senescent. Conversely, cells exposed to 'high' levels of roscovitine became apoptotic. The mechanism of antiapoptosis and senescence with 'low'-dose roscovitine involves augmentation of the antiapoptotic proteins. Conclusions: Data in this study provide a mechanistic explanation of how roscovitine is effective in PKD, and suggest that further study of this agent should focus on assessment of dose response. Furthermore, our discovery of senescence induced by a PKD effective drug suggests a new area of therapeutic investigation in this disease.

Original languageEnglish (US)
Pages (from-to)509-515
Number of pages7
JournalAmerican Journal of Nephrology
Volume29
Issue number6
DOIs
StatePublished - Jun 2009

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Autosomal Dominant Polycystic Kidney
Cell Aging
Epithelial Cells
Apoptosis
Kidney
Proteins
Cyclin-Dependent Kinase Inhibitor p21
Neoplasms
Cyclins
roscovitine
Phosphotransferases
Pharmaceutical Preparations

Keywords

  • Apoptosis
  • Autosomal dominant polycystic kidney disease
  • P21
  • Senescence

ASJC Scopus subject areas

  • Nephrology

Cite this

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title = "Disparate effects of roscovitine on renal tubular epithelial cell apoptosis and senescence: Implications for autosomal dominant polycystic kidney disease",
abstract = "Background/Aims: Control of apoptosis in autosomal dominant polycystic kidney disease (ADPKD) and in at least some cancers is likely regulated by the endogenous cyclin kinase inhibitor p21, levels of this protein being decreased in ADPKD and increased in many malignancies. The cyclin kinase inhibitor roscovitine has shown efficacy in treatment of murine PKD. We asked how a single agent can be efficacious in both PKD and cancer. Methods: Renal tubular epithelial cells were incubated at diverse roscovitine concentrations; apoptosis and senescence were measured. Subsequently, levels of pro- and antiapoptotic proteins were evaluated. Results: Renal tubular epithelial cells exposed to 'low' concentrations of roscovitine showed minimal apoptosis in association with markedly increased levels of the antiapoptotic protein p21, and these cells became senescent. Conversely, cells exposed to 'high' levels of roscovitine became apoptotic. The mechanism of antiapoptosis and senescence with 'low'-dose roscovitine involves augmentation of the antiapoptotic proteins. Conclusions: Data in this study provide a mechanistic explanation of how roscovitine is effective in PKD, and suggest that further study of this agent should focus on assessment of dose response. Furthermore, our discovery of senescence induced by a PKD effective drug suggests a new area of therapeutic investigation in this disease.",
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T2 - Implications for autosomal dominant polycystic kidney disease

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AU - Park, See Hyoung

AU - Weiss, Robert H

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N2 - Background/Aims: Control of apoptosis in autosomal dominant polycystic kidney disease (ADPKD) and in at least some cancers is likely regulated by the endogenous cyclin kinase inhibitor p21, levels of this protein being decreased in ADPKD and increased in many malignancies. The cyclin kinase inhibitor roscovitine has shown efficacy in treatment of murine PKD. We asked how a single agent can be efficacious in both PKD and cancer. Methods: Renal tubular epithelial cells were incubated at diverse roscovitine concentrations; apoptosis and senescence were measured. Subsequently, levels of pro- and antiapoptotic proteins were evaluated. Results: Renal tubular epithelial cells exposed to 'low' concentrations of roscovitine showed minimal apoptosis in association with markedly increased levels of the antiapoptotic protein p21, and these cells became senescent. Conversely, cells exposed to 'high' levels of roscovitine became apoptotic. The mechanism of antiapoptosis and senescence with 'low'-dose roscovitine involves augmentation of the antiapoptotic proteins. Conclusions: Data in this study provide a mechanistic explanation of how roscovitine is effective in PKD, and suggest that further study of this agent should focus on assessment of dose response. Furthermore, our discovery of senescence induced by a PKD effective drug suggests a new area of therapeutic investigation in this disease.

AB - Background/Aims: Control of apoptosis in autosomal dominant polycystic kidney disease (ADPKD) and in at least some cancers is likely regulated by the endogenous cyclin kinase inhibitor p21, levels of this protein being decreased in ADPKD and increased in many malignancies. The cyclin kinase inhibitor roscovitine has shown efficacy in treatment of murine PKD. We asked how a single agent can be efficacious in both PKD and cancer. Methods: Renal tubular epithelial cells were incubated at diverse roscovitine concentrations; apoptosis and senescence were measured. Subsequently, levels of pro- and antiapoptotic proteins were evaluated. Results: Renal tubular epithelial cells exposed to 'low' concentrations of roscovitine showed minimal apoptosis in association with markedly increased levels of the antiapoptotic protein p21, and these cells became senescent. Conversely, cells exposed to 'high' levels of roscovitine became apoptotic. The mechanism of antiapoptosis and senescence with 'low'-dose roscovitine involves augmentation of the antiapoptotic proteins. Conclusions: Data in this study provide a mechanistic explanation of how roscovitine is effective in PKD, and suggest that further study of this agent should focus on assessment of dose response. Furthermore, our discovery of senescence induced by a PKD effective drug suggests a new area of therapeutic investigation in this disease.

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