Pathogenic Sequence for Dissecting Aneurysm Formation in a Hypomorphic Polycystic Kidney Disease 1 Mouse Model

Abstract

Objective-Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a multi-system disorder characterized by progressive cyst formation in the kidneys. Serious complications of ADPKD are intracranial and aortic aneurysms. The condition is mainly caused by mutations in the PKD1 or PKD2 gene. We have carefully analyzed vascular remodeling in hypomorphic Pkd1 nl/nL mouse model with dissecting aneurysms in the aorta. Methods and Results-Quantitative real-time polymerase chain reaction revealed that in the aorta the expression of normal Pkd1 is reduced to approximately 26%. Using (immuno)histochemistry we have characterized the pathogenetic sequence for dissecting aneurysm formation. The aorta shows regions with accumulation of matrix components between the elastin lamellae. This is followed by increased numbers of smooth muscle cells and locally weakening of the media.In the intima, accumulation of matrix components and detachment of endothelial cells from the elastin lamellae results in a tear. The combination of weak media and a tear in the intima leads to rupture of the vessel wall resulting in intramural bleeding. Conclusions-The Pkd1nl/nl mouse reveals that polycystin1 is implicated in maintenance of the vessel wall structural integrity, and it is a useful model for dissecting aneurysm formation studies. A utosomal Dominant Polycystic Disease (ADPKD) is one of the most common genetic diseases. ADPKD affects 1 in 1000 individuals and is characterized by progressive development of renal cysts and an increased risk of aneurysm formation. The prevalence of cerebral aneurysms in ADPKD patients is approximately 10-fold higher than in the general population and about 27% among ADPKD patients with a family history for aneurysms. 1,2 The few clinical studies done to determine the frequency of aortic aneurysms in ADPKD, suggest a prevalence varying from 1% to 10% in ADPKD patients. [3][4][5] Furthermore, a gene expression profile study revealed a decrease of PKD1 expression in dissected human aortas. 6 ADPKD has been associated with mutations in the PKD1 or PKD2 gene, encoding the proteins polycystin1 and polycystin2. Both genes are expressed in the smooth muscle cells (SMCs) and endothelial cells (ECs) of the blood vessel. 7-9 At present, however, hardly any histopathologic analyses on dissections and aneurysms in ADPKD have been performed.Several Pkd1 and Pkd2 knock-out mouse models have been generated, however knock-out embryos die at embryonic days 13.5 to 14.5 from a primary cardiovascular defect. 9 -12 These embryos show edema, focal vascular leaks, and hemorrhage. The fact that these mice die in utero withholds the possibility to study aneurysm formation in ADPKD. Recently, we have generated a Pkd1 hypomorphic mouse model, Pkd1 nl/nl , with reduced Pkd1 transcripts in the kidneys. 13 Pkd1 nl/nl mice are viable, and the majority of the animals die within 1 to 2 months after birth. These mice show dissecting aneurysms and cysts in kidneys, liver, and pancreas, which is in line with the pathogenic features found in the...

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

“…16 These mice showed dissecting aneurysm formation with very prominent abnormalities in the media and mild intima involvement. In addition, they have severe polycystic kidney disease.…”

“…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.…”

“…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. As SMCs is the most abundant cell type in the media, we set out to study the effect of Pkd1 gene disruption in vascular SMCs on blood vessel function.…”

Autosomal Dominant Polycystic Kidney Disease and Intracranial Aneurysms: Is There an Increased Risk of Treatment?

“…16,17 Abnormalities of these genes in mouse models correspond with increased rates of arterial dissection, arterial rupture, and intracranial vascular abnormalities. 18 To our knowledge, only 1 study to date has investigated whether these issues engender an increased risk when treating intracranial aneurysms (whether by endovascular coiling or surgical clipping). 2 The purpose of this investigation was to assess whether ADPCKD confers an increased periand immediate postprocedural risk of aneurysm coiling and clipping.…”

Should Patients with Autosomal Dominant Polycystic Kidney Disease Be Screened for Cerebral Aneurysms?

“…32,33 Abnormalities of these genes in mouse models correspond with increased rates of arterial dissection, arterial rupture, and intracranial vascular abnormalities. 34 There is some evidence that the location of the genetic mutation may help prognosticate risk for IA in patients with ADPCKD (mutations in the 5Ј region of PKD1 pose a higher risk than those at the 3Ј end), though further investigation would be needed before this information could be used in a clinical setting. 35 Traditionally, the criterion standard for IA evaluation has been conventional angiography or DSA, which yields a high spatial resolution of 0.1-mm 2 pixels, optimum contrast due to direct intra-arterial bolus delivery with background subtraction, and high temporal resolution (2-6 frames/s) that can depict flow patterns within an aneurysm.…”