CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) and other forms of PKD are associated with dysregulated cell cycle and proliferation. Although no effective therapy for the treatment of PKD is currently available, possible mechanism-based approaches are beginning to emerge. A therapeutic intervention targeting aberrant cilia-cell cycle connection using CDK-inhibitor R-roscovitine showed effective arrest of PKD in jck and cpk models that are not orthologous to human ADPKD. To evaluate whether CDK inhibition approach will translate into efficacy in an orthologous model of ADPKD, we tested R-roscovitine and its derivative S-CR8 in a model with a conditionally inactivated Pkd1 gene (Pkd1 cKO). Similar to ADPKD, Pkd1 cKO mice developed renal and hepatic cysts. Treatment of Pkd1 cKO mice with R-roscovitine and its more potent and selective analog S-CR8 significantly reduced renal and hepatic cystogenesis and attenuated kidney function decline. Mechanism of action studies demonstrated effective blockade of cell cycle and proliferation and reduction of apoptosis. Together, these data validate CDK inhibition as a novel and effective approach for the treatment of ADPKD.

Keywords: :

• animal model
• therapy
• cell division
• cell cycle
• proliferation
• apoptosis
• cyclin-dependent kinases

Disclosure of Potential Conflicts of Interest

L.M. is co-inventor on the roscovitine patent. L.M., H.G. and N.O. are co-inventors of the CR8 patent. L.M. and H.G. are co-founders of ManRos Therapeutics, which has an exclusive license on the CR8 patent.

Acknowledgments

The authors would like to thank Hervé Husson and Kathy W. Klinger for stimulating discussions. L.M. was supported by grants from the Polycystic Kidney Foundation and from “la Foundation PKD France.”