title: Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis.
abstract: 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.
authors.affiliation: Department of Rare Diseases, Sanofi-Genzyme R&D Center, 49 New York Avenue, Framingham, MA 01701, USA.
authors.forename: Hervé
authors.initials: H
authors.lastname: Husson
authors.affiliation: Department of Rare Diseases, Sanofi-Genzyme R&D Center, 49 New York Avenue, Framingham, MA 01701, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Moreno
authors.affiliation: Department of Rare Diseases, Sanofi-Genzyme R&D Center, 49 New York Avenue, Framingham, MA 01701, USA.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Smith
authors.affiliation: Department of Rare Diseases, Sanofi-Genzyme R&D Center, 49 New York Avenue, Framingham, MA 01701, USA.
authors.forename: Mandy M
authors.initials: MM
authors.lastname: Smith
authors.affiliation: Department of Rare Diseases, Sanofi-Genzyme R&D Center, 49 New York Avenue, Framingham, MA 01701, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Russo
authors.affiliation: McLaughlin Research Institute, 1520 23rd Street South, Great Falls, Montana 59405, USA.
authors.forename: Rose
authors.initials: R
authors.lastname: Pitstick
authors.affiliation: Harvard Institutes of Medicine, 4 Blackfan Circle HIM568, Boston, MA 02115, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Sergeev
authors.affiliation: Department of Rare Diseases, Sanofi-Genzyme R&D Center, 49 New York Avenue, Framingham, MA 01701, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ledbetter
authors.affiliation: Department of Rare Diseases, Sanofi-Genzyme R&D Center, 49 New York Avenue, Framingham, MA 01701, USA.
authors.forename: Nikolay O
authors.initials: NO
authors.lastname: Bukanov
authors.affiliation: Department of Biological Mass Spectrometry & Biomarker Research, Sanofi-Genzyme R&D Center, 1 Mountain Road, Framingham, MA 01701, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Lane
authors.affiliation: Department of Biological Mass Spectrometry & Biomarker Research, Sanofi-Genzyme R&D Center, 1 Mountain Road, Framingham, MA 01701, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Zhang
authors.affiliation: ManRos Therapeutics, Hotel de Recherche-Centre de Perharidy, 29680 Roscoff, France.
authors.forename: Katy
authors.initials: K
authors.lastname: Billot
authors.affiliation: McLaughlin Research Institute, 1520 23rd Street South, Great Falls, Montana 59405, USA.
authors.forename: George
authors.initials: G
authors.lastname: Carlson
authors.affiliation: Harvard Institutes of Medicine, 4 Blackfan Circle HIM568, Boston, MA 02115, USA.
authors.forename: Jagesh
authors.initials: J
authors.lastname: Shah
authors.affiliation: ManRos Therapeutics, Hotel de Recherche-Centre de Perharidy, 29680 Roscoff, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, 1900 9th Avenue, Seattle, WA 98101, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Beier
authors.affiliation: Department of Rare Diseases, Sanofi-Genzyme R&D Center, 49 New York Avenue, Framingham, MA 01701, USA oxana.beskrovnaya@genzyme.com.
authors.forename: Oxana
authors.initials: O
authors.lastname: Ibraghimov-Beskrovnaya
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002923:Cilia / Q000187:drug effects* / Q000473:pathology; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics*; D004195:Disease Models, Animal; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011687:Purines / Q000008:administration & dosage; D000077546:Roscovitine; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011687:Purines; D014404:Tubulin; C095114:collapsin response mediator protein-2; D000077546:Roscovitine; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human