Murine autosomal recessive polycystic kidney disease with multiorgan involvement induced by the cpk gene.

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.

Modification of disease progression in rats with inherited polycystic kidney disease.

The most common inherited form of human polycystic kidney disease (PKD), autosomal dominant PKD (ADPKD), is a leading cause of chronic renal failure, but has a variable clinical presentation, with end-stage renal disease occurring in only 25% to 75%. Several findings are consistent with the idea that factors in addition to the primary mutation can affect the progression of cystic change and chronic renal failure in PKD. Epithelial cell proliferation is a central element in the pathogenesis of renal cysts. We postulated that the superimposition of a growth-promoting stimulus might promote more intense proliferation of cystic epithelial cells in inherited cystic disease. To study this, we subjected Han:SPRD rats, with a form of ADPKD that resembles human ADPKD, from 4 until 10 weeks of age to diets designed to promote tubule cell growth. The diets included supplemental NH4Cl (280 mmol/L in drinking water), limited dietary K+ (0.016% of diet; control diet was 1.1% K+), and increased dietary protein (50%; control diet was 23% protein). Treatments designed to promote cell growth caused more aggressive PKD in males and females, worsened azotemia in males, and resulted in azotemia in females (which normally develop PKD but not azotemia at the ages studied). NH4Cl, K+ restriction, and increased dietary protein each caused greater kidney enlargement in males (kidney weight/body weight ratios increased by 35%, 78%, and 105%, respectively) and worsened azotemia in males (serum urea nitrogen values increased by 63%, 514%, and 224%, respectively); in contrast, decreased dietary protein (4%) caused less severe PKD in males (kidney weight/body weight ratios decreased by 43%) and lessened azotemia in males (serum urea nitrogen values decreased by 49%). Similarly, NH4Cl and K+ restriction caused greater kidney enlargement in females (kidney weight/body weight ratios increased by 206% and 203%, respectively) and caused azotemia in females (serum urea nitrogen values increased by 177% and 430%, respectively). On the basis of these results, we conclude that growth-promoting stimuli can alter the expression of hereditary renal cystic disease. These findings demonstrate that the progression of hereditary renal cystic disease can be altered by factors in addition to the primary genetic defect.

Autosomal-dominant polycystic kidney disease in the rat.

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.