Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of autosomal recessive polycystic kidney disease

Scott S. Williams, Patricia Cobo-Stark, Leighton R James, Stefan Somlo, Peter Igarashi

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)733-741
Number of pages9
JournalPediatric Nephrology
Volume23
Issue number5
DOIs
StatePublished - May 1 2008
Externally publishedYes

Fingerprint

Autosomal Recessive Polycystic Kidney
Pancreatic Cyst
Cysts
Kidney
Galactosidases
Dilatation
Exons
Cystic Kidney Diseases
Lac Operon
Pancreatic Ducts
Liver
Liver Function Tests
Homologous Recombination
Blood Urea Nitrogen
Bile Ducts
Reporter Genes
Knockout Mice
Pancreas
Fibrosis
Animal Models

Keywords

  • ARPKD
  • Biliary ductal plate malformations
  • Pkhd1
  • Polycystic kidney disease

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Nephrology

Cite this

Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of autosomal recessive polycystic kidney disease. / Williams, Scott S.; Cobo-Stark, Patricia; James, Leighton R; Somlo, Stefan; Igarashi, Peter.

In: Pediatric Nephrology, Vol. 23, No. 5, 01.05.2008, p. 733-741.

Research output: Contribution to journalArticle

Williams, Scott S. ; Cobo-Stark, Patricia ; James, Leighton R ; Somlo, Stefan ; Igarashi, Peter. / Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of autosomal recessive polycystic kidney disease. In: Pediatric Nephrology. 2008 ; Vol. 23, No. 5. pp. 733-741.
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