Mutation Database
Autosomal Recessive Polycystic Kidney Disease
(ARPKD/PKHD1)

In cooperation with Reinhard Büttner's group we are currently recapitulating the human genotypes in PKD mouse models. We are using these models to better understand the function of the PKD proteins as well as their genetic and physical interactions. Following our success in characterising the murine Pkhd1 orthologue, we aimed to investigate the role of polyductin during mouse embryonic development. We constructed mice with a targeted Pkhd1 germline mutation. Mutant mice showed normal development and fertility, normal renal and hepatocellular function. Surprisingly, no polycystic transformation of the kidneys were detected. In contrast, hepatic sections revealed severe malformation of the ductal plate paralleling changes observed in human ARPKD. We demonstrated further progression in elder mice with massive bile duct proliferation and ectasia with significant fibrosis of the portal tracts. We found continued collagen I and III synthesis in portal tracts of Pkhd1ex40-deficient mice and in human ARPKD patients. We conclude that the persistance of embryonic ductal plates in ARPKD patients and in our Pkhd1 mutated mice results from deficient PKHD1 function and triggers continued cholangiocyte proliferation, TGFß1 expression and portal collagen synthesis.

Figure 1: Progressive portal fibrosis, TGF-β1 expression and proliferation of cholangiocytes in Pkhd1delex40 mice. Panels show indirect peroxidase immunostainings of liver sections with primary antibodies indicated in the left margin. (A, C, E) Wild-type mice, (B, D, F) Pkhd1delex40 mice. PV, portal vein; bd, bile duct (from Moser et al., Hepatology 41:1113-1121, 2005).

Figure 2: Histological analysis of liver changes in Pkhd1delex40 mice. Liver sections from adult wild-type littermates 14 weeks after birth (A-B), from Pkhd1delex40 mice 1 day (C-D), 5 weeks (E-F), and 14 weeks after birth (G-H). Panels A, C, E, and G show hematoxylin staining, and panels B, D, F, and H Sirius staining. PV, portal vein; bd, bile duct; lob, hepatic lobule; cv, hepatic central vein (from Moser et al., Hepatology 41:1113-1121, 2005).