Targeting dysregulated cell cycle and apoptosis for polycystic kidney disease therapy.
Polycystic kidneys diseases (PKDs) represent a group of disorders characterized by the growth of fluid filled cysts in kidneys and other organs. No effective treatment is currently available for PKDs. A link between dysfunctional cilia and cell cycle regulation has been recently discovered as the most proximal trigger of cystogenesis. We examined the benefit of therapeutic correction of the cell cycle dysregulation in PKD with the cyclin dependent kinase (CDK) inhibitor roscovitine. Our data show that CDK inhibition results in the robust, long lasting arrest of cystogenesis in both slowly progressive and aggressive mouse models of PKD. Dissection of the molecular mechanism of CDK inhibitor action shows effective cell cycle arrest, transcriptional inhibition and attenuation of apoptosis. Roscovitine treatment has proven highly effective in preserving the renal function in treated animals. We also detected significant downregulation of cAMP and aquaporin 2 in treated kidneys, suggesting the effect of CDK inhibition on preservation of epithelial differentiation. CDK inhibition was shown to be efficacious in multiple other types of renal diseases with abnormal cell cycle and proliferation. Thus, therapies directly targeting coordinate regulation of proliferation and apoptosis are emerging as effective approaches to treat multiple renal diseases.
Ibraghimov-Beskrovnaya
Oxana
O
Genzyme Corporation, Framingham, Massachusetts 01701, USA. oxana.beskrovnaya@genzyme.com
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018816:Genes, cdc / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D007690:Polycystic Kidney Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use; D000077546:Roscovitine
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases