TY - JOUR
T1 - Pkd1 transgenic mice
T2 - Adult model of polycystic kidney disease with extrarenal and renal phenotypes
AU - Kurbegovic, Almira
AU - Côté, Olivier
AU - Couillard, Martin
AU - Ward, Christopher J.
AU - Harris, Peter C.
AU - Trudel, Marie
PY - 2010/1/6
Y1 - 2010/1/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77952491724&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77952491724&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddp588
DO - 10.1093/hmg/ddp588
M3 - Article
C2 - 20053665
AN - SCOPUS:77952491724
SN - 0964-6906
VL - 19
SP - 1174
EP - 1189
JO - Human molecular genetics
JF - Human molecular genetics
IS - 7
M1 - ddp588
ER -