DIFFERENTIAL RESCUE OF THE RENAL AND HEPATIC-DISEASE IN AN AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY-DISEASE MOUSE MUTANT - A NEW MODEL TO STUDY THE LIVER LESION

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by biliary and renal lesions that produce significant morbidity and m ortality. The biliary ductal ectasia and hepatic portal fibrosis assoc iated with ARPKD have not been well studied even though such lesions m arkedly affect the clinical course of patients after renal replacement therapy such as dialysis or transplantation, Here we describe the gen eration of a new mouse model to study the hepatic lesions associated w ith polycystic kidney disease This model was generated by differential ly rescuing the renal pathology in the orpk mutant mouse that displays a hepatorenal pathology that is similar to that seen in human patient s with ARPKD. This was accomplished by expressing, as a transgene in t he mutant animals, the cloned wild-type version of the gene associated with the mutant locus in this line of mice. Although renal function i n the rescue animals is normal, the liver still exhibits biliary and d uctular hyperplasia along with varying degrees of hepatic portal fibro sis that is indistinguishable from that in the mutant animals. Most im portant, the rescue animals survive significantly longer than mutants and will permit a more detailed analysis of the clinical and cellular pathophysiology of the hepatic defect associated with this disease.