TY - JOUR
T1 - Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of autosomal recessive polycystic kidney disease
AU - Williams, Scott S.
AU - Cobo-Stark, Patricia
AU - James, Leighton R.
AU - Somlo, Stefan
AU - Igarashi, Peter
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) grants R01DK42921 and R01DK67565 and the UT Southwestern O’Brien Kidney Research Core Center (NIH P30DK079328).
PY - 2008/5
Y1 - 2008/5
N2 - Mutations in PKHD1 cause autosomal recessive polycystic kidney disease (ARPKD). We produced a mouse model of ARPKD by replacing exons 1-3 of Pkhd1 with a lacZ reporter gene utilizing homologous recombination. This approach yielded heterozygous Pkhd1lacZ/+ mice, that expressed β-galactosidase in tissues where Pkhd1 is normally expressed, and homozygous Pkhd1lacZ/lacZ knockout mice. Heterozygous Pkhd1lacZ/+ mice expressed β-galactosidase in the kidney, liver, and pancreas. Homozygous Pkhd1lacZ/lacZ mice lacked Pkhd1 expression and developed progressive renal cystic disease involving the proximal tubules, collecting ducts, and glomeruli. In the liver, inactivation of Pkhd1 resulted in dilatation of the bile ducts and periportal fibrosis. Dilatation of pancreatic exocrine ducts was uniformly seen in Pkhd1lacZ/lacZ mice, with pancreatic cysts arising less frequently. The expression of β-galactosidase, Pkd1, and Pkd2 was reduced in the kidneys of Pkhd1lacZ/lacZ mice compared with wild-type littermates, but no changes in blood urea nitrogen (BUN) or liver function tests were observed. Collectively, these results indicate that deletion of exons 1-3 leads to loss of Pkhd1 expression and results in kidney cysts, pancreatic cysts, and biliary ductal plate malformations. The Pkhd1lacZ/lacZ mouse represents a new orthologous animal model for studying the pathogenesis of kidney cysts and biliary dysgenesis that characterize human ARPKD.
AB - Mutations in PKHD1 cause autosomal recessive polycystic kidney disease (ARPKD). We produced a mouse model of ARPKD by replacing exons 1-3 of Pkhd1 with a lacZ reporter gene utilizing homologous recombination. This approach yielded heterozygous Pkhd1lacZ/+ mice, that expressed β-galactosidase in tissues where Pkhd1 is normally expressed, and homozygous Pkhd1lacZ/lacZ knockout mice. Heterozygous Pkhd1lacZ/+ mice expressed β-galactosidase in the kidney, liver, and pancreas. Homozygous Pkhd1lacZ/lacZ mice lacked Pkhd1 expression and developed progressive renal cystic disease involving the proximal tubules, collecting ducts, and glomeruli. In the liver, inactivation of Pkhd1 resulted in dilatation of the bile ducts and periportal fibrosis. Dilatation of pancreatic exocrine ducts was uniformly seen in Pkhd1lacZ/lacZ mice, with pancreatic cysts arising less frequently. The expression of β-galactosidase, Pkd1, and Pkd2 was reduced in the kidneys of Pkhd1lacZ/lacZ mice compared with wild-type littermates, but no changes in blood urea nitrogen (BUN) or liver function tests were observed. Collectively, these results indicate that deletion of exons 1-3 leads to loss of Pkhd1 expression and results in kidney cysts, pancreatic cysts, and biliary ductal plate malformations. The Pkhd1lacZ/lacZ mouse represents a new orthologous animal model for studying the pathogenesis of kidney cysts and biliary dysgenesis that characterize human ARPKD.
KW - ARPKD
KW - Biliary ductal plate malformations
KW - Pkhd1
KW - Polycystic kidney disease
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U2 - 10.1007/s00467-007-0735-4
DO - 10.1007/s00467-007-0735-4
M3 - Article
C2 - 18286309
AN - SCOPUS:41749084379
SN - 0931-041X
VL - 23
SP - 733
EP - 741
JO - Pediatric Nephrology
JF - Pediatric Nephrology
IS - 5
ER -