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A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD)
Markus Moser1, Sonja Matthiesen, Jutta Kirfel
1Max-Planck-Institute of Biochemistry, Martinsried, Germany.
Insights
Autosomal recessive polycystic kidney disease (ARPKD) arises from PKHD1 gene mutations. A new mouse model reveals Pkhd1 mutations cause severe bile duct malformations and liver fibrosis, but not kidney disease.
Area of Science:
- Genetics
- Pediatric Nephrology
- Hepatology
Background:
- Autosomal recessive polycystic kidney disease (ARPKD) is a significant cause of childhood morbidity and mortality, linked to mutations in the PKHD1 gene.
- PKHD1 encodes polyductin, a transmembrane protein implicated in ARPKD pathogenesis.
Purpose of the Study:
- To generate and characterize a novel mouse model for ARPKD by targeting the Pkhd1 gene.
- To investigate the role of polyductin in liver and kidney development and disease.
Main Methods:
- Generation of a targeted mouse mutation in Pkhd1 (Pkhd1ex40) via exon skipping.
- Analysis of Pkhd1 transcript modification, bile duct morphology, cholangiocyte proliferation, TGF-beta1 synthesis, collagen deposition, and kidney structure/function.
Main Results:
- Pkhd1ex40 mice exhibit severe intrahepatic bile duct malformations, characterized by persistent cholangiocyte proliferation and TGF-beta1 synthesis.
- Progressive portal fibrosis and portal hypertension develop due to continuous collagen synthesis by mesenchymal cells, without affecting hepatocytes.
- In contrast to human ARPKD, Pkhd1ex40 mice display morphologically and functionally normal kidneys.
Conclusions:
- The Pkhd1ex40 mutation leads to dysgenesis of terminally differentiated bile ducts after embryonic ductal plate formation.
- Polyductin plays a functionally divergent role in liver and kidney, with essential domains for bile duct development not impacting nephrogenesis.
Abstract:
Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of liver- and renal-related morbidity and mortality in childhood. Recently, PKHD1, the gene encoding the transmembrane protein polyductin, was shown to be mutated in ARPKD patients. We here describe the first mouse strain, generated by targeted mutation of Pkhd1. Due to exon skipping, Pkhd1ex40 mice express a modified Pkhd1 transcript and develop severe malformations of intrahepatic bile ducts. Cholangiocytes maintain a proliferative phenotype and continuously synthesize TGF-beta1. Subsequently, mesenchymal cells within the hepatic portal tracts continue to synthesize collagen, resulting in progressive portal fibrosis and portal hypertension. Fibrosis did not involve the hepatic lobules, and we did not observe any pathological changes in morphology or function of hepatocytes. Surprisingly and in contrast to human ARPKD individuals, Pkhd1ex40 mice develop morphologically and functionally normal kidneys. In conclusion,our data indicate that subsequent to formation of the embryonic ductal plate, dysgenesis of terminally differentiated bile ducts occurs in response to the Pkhd1ex40 mutation. The role of polyductin in liver and kidney may be functionally divergent, because protein domains essential for bile duct development do not affect nephrogenesis in our mouse model.
