Pathogenic sequence for dissecting aneurysm formation in a hypomorphic polycystic kidney disease 1 mouse model.
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.


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 Pkd1(nl/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.
Center for Human and Clinical Genetics, Leiden University Medical Center, Postal zone: S-04-P, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
Sabrine
S
Hassane
Nanna
N
Claij
Irma S
IS
Lantinga-van Leeuwen
J Conny
JC
Van Munsteren
Natascha
N
Van Lent
Roeland
R
Hanemaaijer
Martijn H
MH
Breuning
Dorien J M
DJ
Peters
Marco C
MC
DeRuiter
D000784:Aortic Dissection / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology*; D001014:Aortic Aneurysm / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D050396:TRPP Cation Channels / Q000378:metabolism*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology
D012333:RNA, Messenger; D050396:TRPP Cation Channels