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Abstract: FR-PO284

Pathogenic STAT3 Activation in Cystic Kidney and Bile Duct Epithelia of Murine Pkhd1-Knockout

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Ziegler, Wolfgang H., Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
  • Fox, Julia, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
  • Burmester, Hanna, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
  • Hahnenstein, Susanne, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
  • Haffner, Dieter, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany

Loss of fibrocystin function causes autosomal recessive polycystic kidney disease (ARPKD) associated with epithelial defects, cyst formation and fibrosis of kidney and liver. In the mouse model, liver defects are developing independent of gender, while kidney defects are restricted to female mice. Study of fibrocystin function in mouse kidney is hampered by mild cyst development and late onset. Here, we re-analyze the kidney and liver phenotype in Pkhd1-knockout mice of different age in a defined background strain and observe distinct hallmarks of disease development and fibrocystin related signaling.


Targeted mutation Pkhd1-knockout mice in BALB background were maintained within the line. Kidneys and livers of male and female animals, homozygous and heterozygous for the Pkhd1-knockout allele as well as wildtype, were analyzed histologically at 8 weeks and 3 to 9 months of age, with serum and urine samples taken before preparation. We compare signaling in cystic epithelia of both organs to behavior of epithelial cell lines with and without fibrocystin expression.


At 6 and 9 months of age, relative kidney and liver weights were massively increased in homozygous female Pkhd1-knockout mice as compared to heterozygous and wildtype controls. In kidneys, cyst formation at the corticomedullary border led to a significantly increased cystic index in knockout mice associated with pronounced macrophage recruitment and fibrosis peaking at 9 months. In addition, proliferation markers were significantly enhanced and pronounced nuclear localization of phosphorylated STAT3 observed in cyst lining epithelia. In liver, ductal plate malformation and fibrotic remodeling were present already at 3 month of age and independent of gender. Induction of STAT3-dependent signaling was addressed in cystic mouse tissue and in stimulated Pkhd1-knockout cell lines with respective controls.


Maintenance in defined BALB background leads to a murine Pkhd1-knockout model showing progressive cyst formation in liver and kidneys associated with fibrosis and inflammation. Highly activated STAT3 signaling was observed associated with epithelial defects. The Pkhd1-knockout mouse allows analysis of disease related mechanisms and appears suitable for testing of pharmacological interventions.


  • Government Support – Non-U.S.