Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst formation in the kidney, liver, and pancreas and is associated often with cardiovascular abnormalities such as hypertension, mitral valve prolapse, and intracranial aneurysms. It is caused by mutations in PKD1 or PKD2, encoding polycystin-1 and -2, which together form a cell surface nonselective cation ion channel. Pkd2؊͞؊ mice have cysts in the kidney and pancreas and defects in cardiac septation, whereas Pkd1 del34 ؊͞؊ and Pkd1 L ؊͞؊ mice have cysts but no cardiac abnormalities, although vascular fragility was reported in the latter. Here we describe mice carrying a targeted mutation in Pkd1 (Pkd1 del17-21␤geo ), which defines its expression pattern by using a lacZ reporter gene and may identify novel functions for polycystin-1. Although Pkd1 del17-21␤geo ؉͞؊ adult mice develop renal and hepatic cysts, Pkd1 del17-21␤geo ؊͞؊ embryos die at embryonic days 13.5-14.5 from a primary cardiovascular defect that includes double outflow right ventricle, disorganized myocardium, and abnormal atrio-ventricular septation. Skeletal development is also severely compromised. These abnormalities correlate with the major sites of Pkd1 expression. During nephrogenesis, Pkd1 is expressed in maturing tubular epithelial cells from embryonic day 15.5. This expression coincides with the onset of cyst formation in Pkd1 del34 ؊͞؊, Pkd1 L ؊͞؊, and Pkd2؊͞؊ mice, supporting the hypothesis that polycystin-1 and polycystin-2 interact in vivo and that their failure to do so leads to abnormalities in tubule morphology and function.

Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension

“…33 Several other explanations could be given why without additional triggers the hypomorphic Pkd1 nl/nl mice, and also Pkd1 knock-out mice, show structural abnormalities of the blood vessels at neonatal or embryonic stages, respectively, while the SM22;Tie2-Pkd1 del/del mice do not. 4,10,11,16 The genetic background may affect the process of blood vessel remodeling, as the complex mouse models used in this study consisted of a mixture of different genetic backgrounds. Furthermore, low Pkd1 expression in other cell types than SMCs and Ecs, in which Pkd1 is not disrupted in the SM22;Tie2-Pkd1 del/del mice (for instance immune cells), may contribute to the process of aneurysm formation in Pkd1 nl/nl mice, thereby accelerating the process.…”

“…2 Both PKD1 and PKD2 are expressed in a variety of cell types and tissues including renal epithelium, hepatic bile ducts, pancreatic ducts, vascular smooth muscle cells (SMCs) and endothelial cells (ECs). [3][4][5] ADPKD is also associated with cysts in the liver and pancreas as well as cardiovascular complications such as hypertension and aneurysms. 6 High blood pressure is very common in ADPKD, and occurs in the majority of patients before any substantial reduction in renal function is observed.…”

“…Homozygous Pkd1 and Pkd2 knock-out mice die in utero, around embryonic day 15, because of severe cystic disease, vascular defects and/or abnormalities of the placental labyrinth, whereas heterozygous Pkd1 knock-out mice showed minimal renal cyst formation in adulthood. 4,[10][11][12][13][14][15] Furthermore, we described a Pkd1 mouse (hypomorphic) model, with low expression of Pkd1 showing progressive polycystic kidney disease and aortic dissecting aneurysms, indicating that Pkd1 is implicated in the structural integrity and function of the vasculature. 16,17 In the hypomorphic Pkd1 nl,nl mice a very prominent media thickening was seen in most of the animals analyzed.…”

Common regulatory elements in the polycystic kidney disease 1 and 2 promoter regions

“…The finding of Ets1 elements in the promoters of Pkd1 and Pkd2 is of particular interest since the Pkd1 promoter has been shown to direct the expression of a reporter gene in the endothelium of a targeted Pkd1 mouse model. 22 Moreover, ADPKD patients have an increased risk to develop cerebral aneurisms and several Pkd1 and Pkd2 mouse models show cardiovascular abnormalities. 22,41 It is therefore reasonable to speculate that ETS factors play a role in regulating the endothelium-specific expression of the Pkd1 and Pkd2 genes.…”

Autosomal dominant polycystic kidney disease (ADPKD, MIM 173900, PKD1 and PKD2 genes, protein products known as polycystin-1 and polycystin-2)

“…70 The Pkd1 (del17À21bgeo) mutant allele has been used to define the expression pattern of Pkd1 and demonstrates widespread expression in most tissues and cell types with highest levels in vascular smooth muscle cells and cartilage. 67 In common with other cystic mouse mutations such as cpk, orpk and inv, Pkd1 and Pkd2, mutant mice have a defect in cilial function. 71 This provides further evidence for a common mechanism underlying renal cyst formation.…”