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Abstract: TH-PO677

Renal Stones in Mice Compound-Heterozygous for Hypomorphic Pkd1V and Pkd1RC Alleles

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Parnell, Stephen C., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Riddle, Heather A.L., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Qian, Feng, University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Stubbs, Jason R., University of Kansas Medical Center, Kansas City, Kansas, United States
  • Rowe, Peter S. N., University of Kansas Medical Center, Kansas City, Kansas, United States

Disease severity in orthologous mouse models of ADPKD is determined in part by the nature of the Pkd1 mutation. While null mutations cause in utero cyst formation and embryonic lethality, hypomorphic mutations Pkd1V/V and Pkd1RC/RC are sufficient for embryonic survival. Pkd1V/V mice express a mutant form of polycystin-1 that fails to undergo autocatalytic cleavage at its G-protein coupled receptor proteolysis site and develop renal cystic disease postnatally and die between 2-6 weeks of age. Pkd1RC/RC mice express a temperature-sensitive folding mutant with reduced levels of mature protein and can live over a year with mild, slowly progressive cystic disease. The phenotypic consequences of these two distinct hypomorphic Pkd1 mutations together are not known.


Pkd1V/+ and Pkd1RC/+ mice on a C57 background were crossed to produce compound-heterozygous Pkd1V/RC mice. Mice were maintained on breeder diet from birth, and sacrificed at 3 or 26 weeks of age and kidneys analyzed. Presence of renal stones in 26 week old adult mice was determined by micro computed tomography (μCT) analysis of kidneys following euthanasia.


Three week old Pkd1V/RC mice had elevated kidney weight to body weight ratios (15.3 ±0.87) and their kidneys were obviously cystic by visual inspection. To determine the long-term consequences of disease we maintained a cohort of mice to 26 weeks of age. The majority of the mice thrived throughout the duration of the study and had significantly lower kidney weight to body weight ratios compared to 3 week old mice. Visual inspection of kidneys from adult mice revealed the presence of numerous large, white masses immediately underneath the renal surface. Analysis of these kidneys by µCT determined that the masses were mineralized deposits of ~0.5mm diameter present throughout the renal cortex but absent from the medulla.


Pkd1V/RC mice are severely cystic by 3 weeks of age. However, these cystic kidneys retain sufficient function to maintain survival up to 26 weeks of age and presumably beyond. Kidneys from adult mice had mineralized deposits throughout the renal cortex. To our knowledge this is the first known instance of renal stones in a mouse model of ADPKD.


  • NIDDK Support