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

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 approximately 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, Pkd1(TAG) 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 approximately 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, Pkd1(TAG) mice displayed occasional cerebral lesions with evidence of ruptured and unruptured cerebral aneurysms. This Pkd1(TAG) mouse model demonstrates that overexpression of wild-type Pkd1 can trigger the typical adult renal and extrarenal phenotypes resembling human ADPKD.

c-Myc Signalling in the Genetic Mechanism of Polycystic Kidney Disease

“…Strikingly, renal analysis in both the Pkd1TAG and SBPkd1TAG mouse models revealed upregulation of c-Myc mRNA expression and protein that is markedly enhanced in the cystic epithelia (104). Pkd1 dysregulation in these mice promotes cellular responses typical of full-length c-Myc.…”

“…Two orthologous dosage-increased Pkd1 mouse models, including one with extrarenal manifestations, reproduce all of the typical PKD characteristics including fibrosis and inflammation (103,104) (Figure 1). Strikingly, renal analysis in both the Pkd1TAG and SBPkd1TAG mouse models revealed upregulation of c-Myc mRNA expression and protein that is markedly enhanced in the cystic epithelia (104).…”

MicroRNAs Regulate Renal Tubule Maturation through Modulation of Pkd1

“…[20][21][22] Two-fold or higher expression of Pkd1 causes kidney cysts in mice. 23,24 Knockdown of Pkd1 disrupts tubulogenesis in 3D culture. 25 In this study, we found that overexpression of Pkd1 is also sufficient to disrupt tubulogenesis.…”

Cils et morphogenèse cardiaque

“…Chez la souris, la mutation des gènes Pkd1 et Pkd2 conduit à des malformations des valves cardiaques [38], ainsi qu'à des défauts de cloisonnement des chambres cardiaques [38,39]. Dans le cas d'une perte de fonction, un myocarde plus fin a été observé [11,38], alors que la surexpression de Pkd1 (entraînant un niveau 2 à 15 fois supérieur au niveau normal) conduit à un effet inverse d'hypertrophie du myocarde [40], ce qui rappelle la maladie humaine. Lorsque la mutation de Pkd1 est restreinte aux cellules endothéliales [41] ou aux muscles lisses et cardiaque [42], elle ne cause pas de défaut cardiaque, à la différence de la mutation ubiquitaire.…”