Pkd1 transgenic mice: Adult model of polycystic kidney disease with extrarenal and renal phenotypes

Almira Kurbegovic, Olivier Côté, Martin Couillard, Christopher J. Ward, Peter C Harris, Marie Trudel

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

While high levels of Pkd1 expression are detected in tissues of patients with autosomal dominant polycystic kidney disease (ADPKD), it is unclear whether enhanced expression could be a pathogenetic mechanism for this systemic disorder. Three transgenic mouse lines were generated from a Pkd1-BAC modified by introducing a silent tag via homologous recombination to target a sustained wild-type genomic Pkd1 expression within the native tissue and temporal regulation. These mice specifically overexpressed the Pkd1 transgene in extrarenal and renal tissues from ~2- to 15-fold over Pkd1 endogenous levels in a copy-dependent manner. All transgenic mice reproducibly developed tubular and glomerular cysts leading to renal insufficiency. Interestingly, Pkd1TAG mice also exhibited renal fibrosis and calcium deposits in papilla reminiscent of nephrolithiasis as frequently observed in ADPKD. Similar to human ADPKD, these mice consistently displayed hepatic fibrosis and ~15% intrahepatic cysts of the bile ducts affecting females preferentially. Moreover, a significant proportion of mice developed cardiac anomalies with severe left-ventricular hypertrophy, marked aortic arch distention and/or valvular stenosis and calcification that had profound functional impact. Of significance, Pkd1TAG mice displayed occasional cerebral lesions with evidence of ruptured and unruptured cerebral aneurysms. This Pkd1TAG mouse model demonstrates that overexpression of wildtype Pkd1 can trigger the typical adult renal and extrarenal phenotypes resembling human ADPKD.

Original languageEnglish (US)
Article numberddp588
Pages (from-to)1174-1189
Number of pages16
JournalHuman Molecular Genetics
Volume19
Issue number7
DOIs
StatePublished - Jan 6 2010

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Autosomal Dominant Polycystic Kidney
Transgenic Mice
Phenotype
Kidney
Cysts
Fibrosis
Intrahepatic Bile Ducts
Nephrolithiasis
Homologous Recombination
Intracranial Aneurysm
Left Ventricular Hypertrophy
Thoracic Aorta
Transgenes
Renal Insufficiency
Pathologic Constriction
Calcium
Liver

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Pkd1 transgenic mice : Adult model of polycystic kidney disease with extrarenal and renal phenotypes. / Kurbegovic, Almira; Côté, Olivier; Couillard, Martin; Ward, Christopher J.; Harris, Peter C; Trudel, Marie.

In: Human Molecular Genetics, Vol. 19, No. 7, ddp588, 06.01.2010, p. 1174-1189.

Research output: Contribution to journalArticle

Kurbegovic, Almira ; Côté, Olivier ; Couillard, Martin ; Ward, Christopher J. ; Harris, Peter C ; Trudel, Marie. / Pkd1 transgenic mice : Adult model of polycystic kidney disease with extrarenal and renal phenotypes. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 7. pp. 1174-1189.
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