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Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine

Nature volume 444, pages 949–952 (2006)Cite this article

Abstract

Polycystic kidney diseases (PKDs) are primarily characterized by the growth of fluid-filled cysts in renal tubules leading to end-stage renal disease1,2,3. Mutations in the PKD1 or PKD2 genes lead to autosomal dominant PKD (ADPKD), a slowly developing adult form4,5. Autosomal recessive polycystic kidney disease results from mutations in the PKHD1 gene, affects newborn infants and progresses very rapidly6,7. No effective treatment is currently available for PKD. A previously unrecognized site of subcellular localization was recently discovered for all proteins known to be disrupted in PKD: primary cilia8,9. Because ciliary functions seem to be involved in cell cycle regulation, disruption of proteins associated with cilia or centrioles may directly affect the cell cycle and proliferation, resulting in cystic disease10,11,12. We therefore reasoned that the dysregulated cell cycle may be the most proximal cause of cystogenesis, and that intervention targeted at this point could provide significant therapeutic benefit for PKD. Here we show that treatment with the cyclin-dependent kinase (CDK) inhibitor (R)-roscovitine does indeed yield effective arrest of cystic disease in jck and cpk mouse models of PKD. Continuous daily administration of the drug is not required to achieve efficacy; pulse treatment provides a robust, long-lasting effect, indicating potential clinical benefits for a lifelong therapy. Molecular studies of the mechanism of action reveal effective cell-cycle arrest, transcriptional inhibition and attenuation of apoptosis. We found that roscovitine is active against cysts originating from different parts of the nephron, a desirable feature for the treatment of ADPKD, in which cysts form in multiple nephron segments. Our results indicate that inhibition of CDK is a new and effective approach to the treatment of PKD.

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Figure 1: Roscovitine inhibits PKD in jck mice.
Figure 2: Roscovitine effectively attenuates disease progression in cpk mice.
Figure 3: Cell cycle blockade in jck kidney with roscovitine.
Figure 4: Treatment with roscovitine results in decreased apoptosis in jck kidney.

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Acknowledgements

We thank R. Russo, T. Barry and A. Taylor for expert technical assistance, the staff of the Genzyme Department of Comparative Medicine and Histology unit for help with in vivo studies and sample preparations. We are grateful to L. Meijer and H. Galons (CNRS, Roscoff) for providing N6-methyl-(R)-roscovitine. We thank A. Smith, R. Gregory, T. Natoli, H. Husson and J. Leonard for helpful discussions and comments on this manuscript.

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Authors and Affiliations

  1. Cell Biology,

    Nikolay O. Bukanov, Laurie A. Smith, Steven R. Ledbetter & Oxana Ibraghimov-Beskrovnaya

  2. Genetics and Genomics, Genzyme Corporation, Framingham, 5 Mountain Road, Massachusetts, 01701-9322, USA

    Katherine W. Klinger

Authors
  1. Nikolay O. Bukanov
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Correspondence to Oxana Ibraghimov-Beskrovnaya.

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Supplementary information

Supplementary Notes

This file contains Supplementary Methods, Supplementary Figures 2 and 5 with legends and additional references. (DOC 3723 kb)

Supplementary Table 1

Anti-cystic effect of Roscovitine in jck mouse model of PKD. (DOC 100 kb)

Supplementary Table 2

Anti-cystic effect of Roscovitine in cpk mouse model of PKD. (DOC 38 kb)

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Bukanov, N., Smith, L., Klinger, K. et al. Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine. Nature 444, 949–952 (2006). https://doi.org/10.1038/nature05348

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