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Am J Physiol Renal Physiol 294: F73-F83, 2008. First published October 10, 2007; doi:10.1152/ajprenal.00362.2007
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Pkd1 and Nek8 mutations affect cell-cell adhesion and cilia in cysts formed in kidney organ cultures

Departments of ¹Cell Biology and ²Pathology, Genzyme Corporation, Framingham, Massachusetts

Submitted 2 August 2007 ; accepted in final form 9 October 2007

Development of novel therapies for polycystic kidney disease (PKD) requires assays that adequately reflect disease biology and are adaptable to high-throughput screening. Here we describe an embryonic cystic kidney organ culture model and demonstrate that a new mutant allele of the Pkd1 gene (Pkd1^tm1Bdgz) modulates cystogenesis in this model. Cyst formation induced by cAMP is influenced by the dosage of the mutant allele: Pkd1^tm1Bdgz –/– cultures develop a larger cystic area compared with +/+ counterparts, while Pkd1^tm1Bdgz +/– cultures show an intermediate phenotype. A similar relationship between the degree of cystogenesis and mutant gene dosage is seen in cystic kidney organ cultures derived from mice with a mutated Nek8 gene (Nek8^jck). Both Pkd1– and Nek8– cultures display altered cell-cell junctions, with reduced E-cadherin expression and altered desmosomal protein expression, similar to ADPKD epithelia. Additionally, characteristic ciliary abnormalities are identified in cystic kidney cultures, with elevated ciliary polycystin 1 expression in Nek8 homozygous cultures and elevated ciliary Nek8 protein expression in Pkd1 homozygotes. These data suggest that the Nek8 and Pkd1 genes function in a common pathway to regulate cystogenesis. Moreover, compound Pkd1 and Nek8 heterozygous adult mice develop a more aggressive cystic disease than animals with a mutation in either gene alone. Finally, we validate the kidney organ culture cystogenesis assay as a therapeutic testing platform using the CDK inhibitor roscovitine. Therefore, embryonic kidney organ culture represents a relevant model for studying molecular cystogenesis and a rapid tool for the screening for therapies that block cystic growth.

polycystic kidney disease; roscovitine; renal disease

This article has been cited by other articles:

				Y. Cai and S. Somlo Too Much of a Good Thing: Does Nek8 Link Polycystic Kidney Disease and Nephronophthisis? J. Am. Soc. Nephrol., March 1, 2008; 19(3): 418 - 420. [Full Text] [PDF]