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Development of autosomal recessive polycystic kidney disease in BALB/c-cpk/cpk mice
Justin L Ricker1, Vincent H Gattone1, James P Calvet2
1Department of Anatomy & Cell Biology, The University of Kansas Medical Center, Kansas City, Kansas.
Abstract:
Autosomal recessive polycystic kidney disease (ARPKD) is a rare but devastating inherited disease in humans. Various strains of mice that are homozygous for the cpk gene display renal pathology similar to that seen in human ARPKD. The PKD progresses to renal insufficiency, azotemia, and ultimately a uremic death by approximately 3 wk of age. This study characterizes PKD in mice that are homozygous for the cpk gene on a BALB/c inbred mouse background. The BALB/c-cpk/cpk murine model displays renal as well as extrarenal pathology similar to that found in human ARPKD. The renal pathology includes the well-characterized early proximal tubule and, later, massive collecting duct cysts. The extrarenal defects in this murine model include common bile duct dilation, intrahepatic biliary duct cysts with periductal hyperplasia, and pancreatic dysplasia with cysts. Renal mRNA expression of c-myc, a proto-oncogene, and clusterin (SGP-2), a marker associated with immature collecting ducts, decreases during normal development but is upregulated in murine ARPKD. Expression of epidermal growth factor (EGF) mRNA is significantly diminished, whereas EGF receptor mRNA is upregulated in the BALB/c-cpk/cpk kidney compared with phenotypically normal littermates. To determine whether the altered EGF expression contributes to the development of PKD, neonatal mice were treated with exogenous EGF (1 microg/g body wt injected subcutaneously on postnatal days 3 through 9). EGF treatment reduced the relative kidney weight and common bile duct dilation and downregulated renal expression of clusterin and EGF receptor. However, exogenous EGF did not affect the degree of renal failure, the pancreatic pathology, or the misregulated renal expression of c-myc. In summary, the present study characterizes the renal and extrarenal pathology in the BALB/c-cpk/cpk murine model of ARPKD. Renal mRNA expression of EGF is diminished in this mouse model. EGF treatment did not prevent renal failure but ameliorated pathologic changes in the kidney and the biliary ducts of the BALB/c-cpk/cpk mouse.
Insights
Autosomal recessive polycystic kidney disease (ARPKD) in mice shows kidney and bile duct cysts. Epidermal growth factor (EGF) treatment improved some pathology but did not prevent kidney failure in this ARPKD mouse model.
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Pathology
Background:
- Autosomal recessive polycystic kidney disease (ARPKD) is a severe inherited human disorder.
- Murine models, such as the cpk gene mutation, mimic human ARPKD pathology.
- The BALB/c-cpk/cpk mouse strain presents both renal and extrarenal defects.
Purpose of the Study:
- To characterize the renal and extrarenal pathology in the BALB/c-cpk/cpk mouse model of ARPKD.
- To investigate the role of epidermal growth factor (EGF) in the development of ARPKD.
- To assess the therapeutic potential of exogenous EGF in this ARPKD model.
Main Methods:
- Detailed pathological characterization of BALB/c-cpk/cpk mice.
- Analysis of renal mRNA expression for c-myc, clusterin, EGF, and EGF receptor.
- Treatment of neonatal mice with exogenous EGF and subsequent evaluation of pathological and molecular markers.
Main Results:
- BALB/c-cpk/cpk mice exhibited renal cysts and extrarenal defects including biliary duct dilation and pancreatic dysplasia.
- Renal expression of EGF mRNA was diminished, while EGF receptor mRNA was upregulated.
- Exogenous EGF treatment reduced kidney weight and biliary dilation, and downregulated clusterin and EGF receptor expression, but did not improve renal failure or pancreatic pathology.
Conclusions:
- The BALB/c-cpk/cpk mouse is a relevant model for studying ARPKD pathology.
- Diminished EGF expression is a feature of this ARPKD model.
- EGF therapy shows partial amelioration of ARPKD-related pathologies but does not resolve renal failure.