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Abstract: FR-PO988

Adult Inactivation of Pkhd1 Results in Liver Cysts in an ARPKD Mouse Model

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Menezes, Luis F., NIDDK/NIH, Bethesda, Maryland, United States
  • Zhou, Fang, NIDDK/NIH, Bethesda, Maryland, United States
  • Germino, Gregory G., NIDDK/NIH, Bethesda, Maryland, United States

Autosomal recessive polycystic kidney disease (ARPKD; OMIM 263200) is a severe disease of infancy and childhood caused by mutations in PKHD1. A common feature of both human disease and orthologous mouse models is biliary duct cysts with portal tract fibrosis, usually attributed to ductal plate malformation, a developmental disorder. According to this model, immature biliary ducts fail to remodel/involute during embryogenesis, leading to congenital fibrosis and biliary cysts. In this study we tested if adult loss of Pkhd1 could result in biliary cysts and portal fibrosis in mature livers.


The Pkhd1Tm1Ggg (Pkhd1flox3–4) mouse line was crossed to FLPeR mice expressing the FLP1 recombinase (stock 003946, Jackson Laboratories) to remove the neomycin cassette, since previous studies determined that uninduced mice developed liver lesions over time. The resulting Pkhd1delneo.flox3–4 was bred to C57/BL6 tamoxifen-Cre (stock 004682, Jackson Laboratories). A set of 53 Pkhd1delneo.flox3–4 mice with or without transgene cre expression (cre negative: 8 females and 8 males; cre positive: 15 females and 22 males) was induced at 40 days of age by one intraperitoneal injection of 0.2 mg/g tamoxifen and harvested between ages 100 and 328. An additional set of 29 mice was aged without being induced with tamoxifen (cre negative: 4 females and 7 males; cre positive: 9 females and 9 males). Animal body, liver and kidney weights were measured, and the kidney and livers were visually inspected. A subset of samples was embedded for histological analysis.


Uninduced animals and induced cre negative mice had normal kidney and macroscopically normal liver morphology up to 300 days of age. Cre positive animals had enlarged livers with visible cysts starting on day 200 (n=7), progressively more affected with age. Expression of cre recombinase was a statistically significant determinant of liver cystic phenotype (p<0.001) in induced mice. No obvious kidney cysts were detected in any mice, and there was no statistical significance in kidney/body weight between induced animal with or without cre expression.


Adult inactivation of Pkhd1 mimics germline inactivation in causing an ARPKD liver phenotype in a mouse model. This suggests that additional mechanisms, independent of ductal plate remodeling and involution, may play a role in the ARPKD polycystic liver.


  • NIDDK Support