ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

Kidney Week

Abstract: FR-PO985

Post-developmental Inactivation of Pkhd1 Results in Liver Cysts in Mice

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Besse, Whitney E., Yale School of Medicine, New Haven, Connecticut, United States
  • Roosendaal, Charlotte E.J., Yale School of Medicine, New Haven, Connecticut, United States
  • Tian, Xin, Yale School of Medicine, New Haven, Connecticut, United States
  • Gallagher, Rachel, Yale School of Medicine, New Haven, Connecticut, United States
  • Somlo, Stefan, Yale School of Medicine, New Haven, Connecticut, United States

Autosomal recessive polycystic kidney disease (ARPKD), caused by recessive mutations in the PKHD1 gene, is a rare congenital disease characterized by diffusely cystic kidneys and hepatic fibrosis. We recently found genome-wide significant enrichment of adult heterozygous PKHD1 carriers in our cohort of genetically unresolved autosomal dominant polycystic kidney and liver disease (ADPKD/ADPLD). ADPKD/ADPLD cysts originate when over time somatic second hit mutations in scattered cells result in the cellular recessive genotype. In order to explore the hypothesis that, like ADPLD cysts, cysts in PKHD1 carriers could result from post-developmental biallelic loss, we used the Cre;Lox system to inactivate Pkhd1 post-developmentally in mouse liver.


Using a Pkhd1flox allele, originally used to generate the Pkhd1del3-4/del3-4 mouse model, we generated the following mice; Pkhd1fl/fl;UBC-Cre (experimental, n=13) and Pkhd1fl/+;UBC-Cre (littermate controls, n=12). All mice were induced with Tamoxifen at postnatal day 28 for 5 days and aged to 17 weeks. Liver and kidney histology was examined for cystic disease.


Histological analysis performed on experimental (n=8) livers demonstrated polycystic livers with minimal pericystic inflammatory infiltrate, while “control” livers were normal. Anti-cytokeratin 19 (CK19) staining demonstrated the cysts were of biliary origin, consistent with both ARPKD and ADPKD mouse models, with significant increase in the CK19+ cell area percentage [6.1% (n=8) vs. 0.5% (n=8)] and cystic index [15.6% (n=8) vs. 3.0% (n=8)]. The mean liver weight to body weight ratio (LW/BW) for the Pkhd1fl/fl;UBC-Cre animals was 5.8 ± 0.8% (n=13) versus 4.3± 0.6% (n=12) (P<0.0001). These data are comparable to Pkhd1del4/del4, and within range of the ADPKD mouse model Pkd1fl/fl;UBC-Cre with the same age and induction regime. Female mice had the most profound effect (LW/BW, 6.2± 0.4% vs. 3.8± 0.2%, n=5 females each). The Pkhd1fl/fl;UBC-Cre kidneys appeared histologically normal.


Post-developmental inactivation of Pkhd1 results in cystic liver disease indicative that Pkhd1 after development is required for biliary epithelial homeostasis. This finding supports investigation of whether the human polycystic liver disease seen in PKHD1 carriers may indeed fit the ADPKD/ADPLD mechanistic paradigm.


  • Other NIH Support