Kaspareit-Rittinghausen described a rodent model of inherited polycystic kidney disease (PKD), the Han:SPRD rat [1, 2], in which heterozygotes develop renal cysts and renal failure (in males) over several months, whereas homozygous animals develop rapidly progressive renal enlargement that leads to death in a few weeks. In this study, we examined selected elements of the pathogenesis of this disease in heterozygotes and homozygotes from birth to advanced disease. Heterozygous male rats developed slowly progressive renal cystic disease with interstitial fibrosis and azotemia seen by six months of age. Female heterozygotes developed slowly progressive renal cystic disease, but did not develop interstitial fibrosis or azotemia. Epithelial cells lining cyst cavities showed various degrees of morphologic immaturity. Cyst walls also developed basement membrane thickening, especially in areas of cellular immaturity, suggesting an interrelationship between this basement membrane thickening and cellular dedifferentiation. Thickened basement membranes were associated with increased immunoreactivity for type IV collagen, laminin, and fibronectin. Homozygous rats developed massive renal enlargement, marked azotemia, and died near three weeks of age. Renal c-myc proto-oncogene expression was elevated in homozygous cystic infants and in adult heterozygotes. In situ hybridization showed high levels of c-myc mRNA in cyst epithelia, suggesting abnormal regulation of cellular proliferation in the cells lining cysts, as seen in other models of PKD. The Han:SPRD rat is the only well-documented animal model of inherited PKD with an autosomal-dominant inheritance pattern and appears to have several features which resemble human ADPKD.

The cpk gene, when placed on an appropriate mouse strain background, causes multiorgan disease that more closely mimics human ARPKD than when the cpk gene is expressed on the C57BL/6J strain. A gene dose effect is present as cystic pathology is present in kidney and liver of both suckling homozygous (cpk/cpk) and old heterozygous (cpk/+) mice.

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Background Autosomal recessive (AR) polycystic kidney disease (PKD) is characterized in humans and mice as a rapidly progressive, collecting duct cystic disease usually leading to uremia in the neonatal or infantile period. In humans, ARPKD renal pathology can be variable in severity and is associated with the development of prominent bile duct and liver pathology. The C57BL/6J‐cpk/cpk mouse model of ARPKD is the most extensively studied murine model of inherited infantile PKD; however, these mice lack extrarenal pathology. Methods In the present study, the cpk gene was backbreed onto CD1 mice to examine the development of cpk‐induced ARPKD in this outbred mouse background. Resulting cystic offspring were examined morphologically and their serum urea nitrogen levels were assessed. Results The rapid development of PKD in CD1 mice homozygous for the cpk gene appears to be slightly more rapid but otherwise comparable to that seen in inbred C57BL/6J mice. In CD1‐cpk/cpk mice, the principal renal pathological finding is collecting duct cysts, which are lined by a relatively uniform epithelium. This epithelium appears to be relatively undifferentiated based on almost total absence of intercalated cells. Proximal tubule cysts are prominent in the first postnatal week while collecting duct cysts predominate in the later stages of the disease. Extrarenal manifestations of the cpk gene are evident in the CD1 strain and include cysts of pancreatic, common bile, and major hepatic ducts. Intrahepatic bile ducts also have focal dilations. Primary (thymus) and secondary (spleen) lymphoid tissues become hypoplastic as azotemia progresses. The strain‐related variability in renal and liver changes in cpk‐induced ARPKD may reflect the influence of other genes (possibly modifier genes) expressed in this mouse strain. In older CD1‐cpk/+ mice, renal (proximal tubular) cysts and prominent liver cysts (lined by a biliary epithelium) develop, indicating that the heterozygous state (cpk/+ genotype) causes renal and hepatic pathology. Conclusions The cpk gene, when placed on an appropriate mouse strain background, causes multiorgan disease that more closely mimics human ARPKD than when the cpk gene is expressed on the C57BL/6J strain. A gene dose effect is present as cystic pathology is present in kidney and liver of both suckling homozygous (cpk/cpk) and old heterozygous (cpk/+) mice. © 1996 Wiley‐Liss, Inc.