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

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in PKD1 or PKD2 and is the most common single gene disorder resulting in end-stage kidney disease. Since deletion of either Pkd1 or Pkd2 in mice is lethal, conditional alleles have become indispensable tools for studying the pathobiology of ADPKD as well as for preclinical testing. The rapidity of cyst formation in Pkd1 conditional mice depends on the timing of gene inactivation but this has never been formally studied for Pkd2. The objective of the present study was to characterize the kinetics of cystogenesis in a Pkd2 conditional mouse model and to identify associated alterations in gene expression. Here, we show that there is a similar developmental switch in Pkd2 conditional mice with delayed cyst formation after Pkd2 inactivation at or beyond P14. In addition, we find that similar to Pkd1, cystogenesis is associated with differential expression of genes involved in metabolism, cell proliferation and immune response. Our study confirms 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 Pkd2 genotype. In summary, 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 taken into account in any study design using orthologous mouse models with late Pkd2 inactivation.