A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation

J. R. Woollard, R. Punyashtiti, S. Richardson, T. V. Masyuk, S. Whelan, B. Q. Huang, D. J. Lager, Jan Van Deursen, Vicente Torres, V. H. Gattone, Nicholas F La Russo, Peter C Harris, C. J. Ward

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the polycystic kidney and hepatic disease (PKHD1) gene encoding the protein fibrocystin/polyductin. The aim of our study was to produce a mouse model of ARPKD in which there was no functional fibrocystin/polyductin to study the pathophysiology of cystic and fibrocystic disease in renal and non-renal tissues. Exon 2 of the gene was deleted and replaced with a neomycin resistance cassette flanked by loxP sites, which could be subsequently removed by Cre-lox recombinase. Homozygous Pkhd1del2/del2 mice were viable, fertile and exhibited hepatic, pancreatic, and renal abnormalities. The biliary phenotype displayed progressive bile duct dilatation, resulting in grossly cystic and fibrotic livers in all animals. The primary cilia in the bile ducts of these mutant mice had structural abnormalities and were significantly shorter than those of wild-type (WT) animals. The Pkhd1del2/del2 mice often developed pancreatic cysts and some exhibited gross pancreatic enlargement. In the kidneys of affected female mice, there was tubular dilatation of the S3 segment of the proximal tubule (PT) starting at about 9 months of age, whereas male mice had normal kidneys up to 18 months of age. Inbreeding the mutation onto BALBc/J or C57BL/6J background mice resulted in females developing PT dilatation by 3 months of age. These inbred mice will be useful resources for studying the mechanisms underlying the pathogenesis of ARPKD.

Original languageEnglish (US)
Pages (from-to)328-336
Number of pages9
JournalKidney International
Volume72
Issue number3
DOIs
StatePublished - Aug 2007

Fingerprint

Autosomal Recessive Polycystic Kidney
Dilatation
Kidney
Bile Ducts
Liver
Pancreatic Cyst
Polycystic Kidney Diseases
Mutation
Wild Animals
Neomycin
Inbreeding
Cilia
Exons
Phenotype

Keywords

  • ARPKD
  • Fibrocystin
  • Knockout model
  • Mouse
  • Pkhd1
  • Polycystic kidney disease

ASJC Scopus subject areas

  • Nephrology

Cite this

Woollard, J. R., Punyashtiti, R., Richardson, S., Masyuk, T. V., Whelan, S., Huang, B. Q., ... Ward, C. J. (2007). A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation. Kidney International, 72(3), 328-336. https://doi.org/10.1038/sj.ki.5002294

A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation. / Woollard, J. R.; Punyashtiti, R.; Richardson, S.; Masyuk, T. V.; Whelan, S.; Huang, B. Q.; Lager, D. J.; Van Deursen, Jan; Torres, Vicente; Gattone, V. H.; La Russo, Nicholas F; Harris, Peter C; Ward, C. J.

In: Kidney International, Vol. 72, No. 3, 08.2007, p. 328-336.

Research output: Contribution to journalArticle

Woollard, JR, Punyashtiti, R, Richardson, S, Masyuk, TV, Whelan, S, Huang, BQ, Lager, DJ, Van Deursen, J, Torres, V, Gattone, VH, La Russo, NF, Harris, PC & Ward, CJ 2007, 'A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation', Kidney International, vol. 72, no. 3, pp. 328-336. https://doi.org/10.1038/sj.ki.5002294
Woollard, J. R. ; Punyashtiti, R. ; Richardson, S. ; Masyuk, T. V. ; Whelan, S. ; Huang, B. Q. ; Lager, D. J. ; Van Deursen, Jan ; Torres, Vicente ; Gattone, V. H. ; La Russo, Nicholas F ; Harris, Peter C ; Ward, C. J. / A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation. In: Kidney International. 2007 ; Vol. 72, No. 3. pp. 328-336.
@article{e4cfb674f2204179ac5565e634196de1,
title = "A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation",
abstract = "Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the polycystic kidney and hepatic disease (PKHD1) gene encoding the protein fibrocystin/polyductin. The aim of our study was to produce a mouse model of ARPKD in which there was no functional fibrocystin/polyductin to study the pathophysiology of cystic and fibrocystic disease in renal and non-renal tissues. Exon 2 of the gene was deleted and replaced with a neomycin resistance cassette flanked by loxP sites, which could be subsequently removed by Cre-lox recombinase. Homozygous Pkhd1del2/del2 mice were viable, fertile and exhibited hepatic, pancreatic, and renal abnormalities. The biliary phenotype displayed progressive bile duct dilatation, resulting in grossly cystic and fibrotic livers in all animals. The primary cilia in the bile ducts of these mutant mice had structural abnormalities and were significantly shorter than those of wild-type (WT) animals. The Pkhd1del2/del2 mice often developed pancreatic cysts and some exhibited gross pancreatic enlargement. In the kidneys of affected female mice, there was tubular dilatation of the S3 segment of the proximal tubule (PT) starting at about 9 months of age, whereas male mice had normal kidneys up to 18 months of age. Inbreeding the mutation onto BALBc/J or C57BL/6J background mice resulted in females developing PT dilatation by 3 months of age. These inbred mice will be useful resources for studying the mechanisms underlying the pathogenesis of ARPKD.",
keywords = "ARPKD, Fibrocystin, Knockout model, Mouse, Pkhd1, Polycystic kidney disease",
author = "Woollard, {J. R.} and R. Punyashtiti and S. Richardson and Masyuk, {T. V.} and S. Whelan and Huang, {B. Q.} and Lager, {D. J.} and {Van Deursen}, Jan and Vicente Torres and Gattone, {V. H.} and {La Russo}, {Nicholas F} and Harris, {Peter C} and Ward, {C. J.}",
year = "2007",
month = "8",
doi = "10.1038/sj.ki.5002294",
language = "English (US)",
volume = "72",
pages = "328--336",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation

AU - Woollard, J. R.

AU - Punyashtiti, R.

AU - Richardson, S.

AU - Masyuk, T. V.

AU - Whelan, S.

AU - Huang, B. Q.

AU - Lager, D. J.

AU - Van Deursen, Jan

AU - Torres, Vicente

AU - Gattone, V. H.

AU - La Russo, Nicholas F

AU - Harris, Peter C

AU - Ward, C. J.

PY - 2007/8

Y1 - 2007/8

N2 - Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the polycystic kidney and hepatic disease (PKHD1) gene encoding the protein fibrocystin/polyductin. The aim of our study was to produce a mouse model of ARPKD in which there was no functional fibrocystin/polyductin to study the pathophysiology of cystic and fibrocystic disease in renal and non-renal tissues. Exon 2 of the gene was deleted and replaced with a neomycin resistance cassette flanked by loxP sites, which could be subsequently removed by Cre-lox recombinase. Homozygous Pkhd1del2/del2 mice were viable, fertile and exhibited hepatic, pancreatic, and renal abnormalities. The biliary phenotype displayed progressive bile duct dilatation, resulting in grossly cystic and fibrotic livers in all animals. The primary cilia in the bile ducts of these mutant mice had structural abnormalities and were significantly shorter than those of wild-type (WT) animals. The Pkhd1del2/del2 mice often developed pancreatic cysts and some exhibited gross pancreatic enlargement. In the kidneys of affected female mice, there was tubular dilatation of the S3 segment of the proximal tubule (PT) starting at about 9 months of age, whereas male mice had normal kidneys up to 18 months of age. Inbreeding the mutation onto BALBc/J or C57BL/6J background mice resulted in females developing PT dilatation by 3 months of age. These inbred mice will be useful resources for studying the mechanisms underlying the pathogenesis of ARPKD.

AB - Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the polycystic kidney and hepatic disease (PKHD1) gene encoding the protein fibrocystin/polyductin. The aim of our study was to produce a mouse model of ARPKD in which there was no functional fibrocystin/polyductin to study the pathophysiology of cystic and fibrocystic disease in renal and non-renal tissues. Exon 2 of the gene was deleted and replaced with a neomycin resistance cassette flanked by loxP sites, which could be subsequently removed by Cre-lox recombinase. Homozygous Pkhd1del2/del2 mice were viable, fertile and exhibited hepatic, pancreatic, and renal abnormalities. The biliary phenotype displayed progressive bile duct dilatation, resulting in grossly cystic and fibrotic livers in all animals. The primary cilia in the bile ducts of these mutant mice had structural abnormalities and were significantly shorter than those of wild-type (WT) animals. The Pkhd1del2/del2 mice often developed pancreatic cysts and some exhibited gross pancreatic enlargement. In the kidneys of affected female mice, there was tubular dilatation of the S3 segment of the proximal tubule (PT) starting at about 9 months of age, whereas male mice had normal kidneys up to 18 months of age. Inbreeding the mutation onto BALBc/J or C57BL/6J background mice resulted in females developing PT dilatation by 3 months of age. These inbred mice will be useful resources for studying the mechanisms underlying the pathogenesis of ARPKD.

KW - ARPKD

KW - Fibrocystin

KW - Knockout model

KW - Mouse

KW - Pkhd1

KW - Polycystic kidney disease

UR - http://www.scopus.com/inward/record.url?scp=34547462511&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547462511&partnerID=8YFLogxK

U2 - 10.1038/sj.ki.5002294

DO - 10.1038/sj.ki.5002294

M3 - Article

VL - 72

SP - 328

EP - 336

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 3

ER -