Inactivation of Pkd2 in adult mice results in delayed cyst formation and identifies sex as a major modifier of disease severity.

INTRODUCTION Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in PKD1 or PKD2 and is the most common single-gene disorder resulting in kidney failure. Since deletion of either Pkd1 or Pkd2 in mice is embryonically lethal, conditional alleles have become indispensable tools for studying the pathobiology of ADPKD and for preclinical testing. The rapidity of cyst formation in Pkd1 conditional mice depends on the timing of gene inactivation, but this has never been systematically studied for Pkd2. Here, we characterize the kinetics of cystogenesis in a Pkd2 conditional mouse model and identify associated alterations in gene expression. METHODS Using a conditional mouse model, we inactivated Pkd2 at different postnatal stages and characterized the severity of cyst formation. Additionally, we performed RNA-sequencing analysis to identify gene expression changes associated with Pkd2 loss in males and females. RESULTS There is a similar developmental switch in Pkd2 conditional mice with delayed cyst formation after Pkd2 inactivation at or beyond postnatal day 14. Like Pkd1 models, cystogenesis is associated with differential expression of genes involved in metabolism, cell proliferation, and immune response. We confirm that sex is a key modifier of ADPKD progression with differences in disease severity occurring in the context of significant transcriptional differences between males and females that are independent of the Pkd2 genotype. CONCLUSIONS Pkd2 conditional mice are a useful model for understanding ADPKD pathogenesis and for testing therapeutics. Our data highlight the importance of sex as a biological variable that should be considered in any study design using orthologous mouse models with late Pkd2 inactivation.