Molecular and genetic analysis of the orpk mouse model of polycystic kidney disease : searching for treatments and modifer genes

The orpk line of mice was previously identified as a unique model for human polycystic kidney disease. The most prominent phenotype is the invariable development of bilateral polycystic kidneys and abnormalities in the intrahepatic biliary tract and pancreas.

Taxol has been reported to be of therapeutic benefit in the cpk mouse model of polycystic kidney disease. The effects of taxol treatment on the development of renal cysts and biliary dysplasia/hyperplasia in the orpk mouse mutant were studied. There were no significant differences between the treatment and control groups with respect to weight gain, survival, urine to serum osmolality ratio, and serum concentration of liver enzymes. Moreover, the renal cystic development and biliary hyperplasia was not affected by taxol treatment in the orpk mutant animals.

There are marked differences in the phenotypic expression of the orpk mutation when bred on different genetic backgrounds. In the FVB/N genetic background, the phenotype is very severe in the kidney, liver, and pancreas lesions. To better evaluate how genetic background might influence the expressivity of the orpk phenotype, the transgene was made congenic on the C3H genetic background. Congenic orpk-C3H mutant mice have a much less sever phenotype identical to that initially observed in the first generation backcross to C3H. The kidney lesions are morphologically similar in the orpk- C3H mutant mice, but they develop renal cysts at a slower rate and have fewer cysts at all stages of cyst development. These animals also retain their renal concentrating ability. The liver lesions in the orpk-C3H mutant animals are less aggressive and are characterized by multifocal biliary hyperplasia, dysplasia, and portal fibrosis isolated to the portal triad regions. The significant lesions when the orpk mutation is on a different genetic background suggests the presence of important modifier genes that vary in the FVB/N and C3H genetic backgrounds. Whole genome quantitative trait analysis was performed to determine the chromosomal location of the modifier genes that influence the phenotypic expression of the orpk in the FVB/N and C3H genetic backgrounds. The percent of the kidney that is cystic was used as a quantitative trait that reflects the kidney phenotype. Serum concentration of alkaline phosphatase was used as a quantitative trait that reflects the liver phenotype. A backcross between (orpk- FVB X C3H) F1 tg/+ mice and orpk-FVB tg/+ mice was performed and 100 tg/tg progeny were scored for the kidney and liver traits.

Whole genome quantitative trait loci mapping of 40 selected backcross tg/tg progeny (20 with mild kidney scores and 20 with severe kidney scores) identified three chromosomal intervals that segregated with the severe kidney phenotype. Whole genome quantitative trait loci mapping of 40 selected backcross tg/tg progeny (20 with mild liver scores and 20 with severe liver scores) identified one DMA marker that segregated with the severe liver phenotype. Further characterization of these intervals with low resolution and fine mapping may provide candidate modifying loci that will provide information in understanding the pathogenesis of polycystic kidney disease.