Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis
| Autor: | Katy Billot, Mandy M. Smith, Rose Pitstick, Jagesh V. Shah, Kate Zhang, George A. Carlson, Laurent Meijer, Hervé Husson, Laurie A. Smith, Oxana Ibraghimov-Beskrovnaya, Monica Lane, Nikolay O. Bukanov, Steven R. Ledbetter, Ryan J. Russo, Sarah Moreno, David R. Beier, Mikhail Sergeev |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Cellular differentiation Nerve Tissue Proteins Biology Kidney Kidney cysts Mice 03 medical and health sciences 0302 clinical medicine Tubulin Nephronophthisis Internal medicine Ciliogenesis Roscovitine Genetics medicine Polycystic kidney disease Animals Humans Cilia Molecular Biology Genetics (clinical) Cystic kidney Polycystic Kidney Diseases Cilium Cell Differentiation Cyclin-Dependent Kinase 5 Articles General Medicine medicine.disease Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure Purines 030220 oncology & carcinogenesis Cancer research Intercellular Signaling Peptides and Proteins Kidney Failure Chronic medicine.symptom |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Polycystic kidney diseases (PKDs) comprise a subgroup of ciliopathies characterized by the formation of fluid-filled kidney cysts and progression to end-stage renal disease. A mechanistic understanding of cystogenesis is crucial for the development of viable therapeutic options. Here, we identify CDK5, a kinase active in post mitotic cells, as a new and important mediator of PKD progression. We show that long-lasting attenuation of PKD in the juvenile cystic kidneys (jck) mouse model of nephronophthisis by pharmacological inhibition of CDK5 using either R-roscovitine or S-CR8 is accompanied by sustained shortening of cilia and a more normal epithelial phenotype, suggesting this treatment results in a reprogramming of cellular differentiation. Also, a knock down of Cdk5 in jck cells using small interfering RNA results in significant shortening of ciliary length, similar to what we observed with R-roscovitine. Finally, conditional inactivation of Cdk5 in the jck mice significantly attenuates cystic disease progression and is associated with shortening of ciliary length as well as restoration of cellular differentiation. Our results suggest that CDK5 may regulate ciliary length by affecting tubulin dynamics via its substrate collapsin response mediator protein 2. Taken together, our data support therapeutic approaches aimed at restoration of ciliogenesis and cellular differentiation as a promising strategy for the treatment of renal cystic diseases. |
| Databáze: | OpenAIRE |
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