Enhanced intracranial aneurysm development in a rat model of polycystic kidney disease

Abstract

Aim Polycystic kidney disease (PKD) patients have a high intracranial aneurysms (IAs) incidence and risk of rupture. The mechanisms that make PKD patients more vulnerable to IA disease are still not completely understood. The PCK rat is a well-known PKD model and has been extensively used to study cyst development and kidney damage. Here, we used this rat model to study IA induction and vulnerability. Methods and results IAs were induced in wild-type (WT) and PCK rats and their incidence was followed. Variation in the anatomy of the circle of Willis was studied in PCK rats and PKD patients. Immunohistochemistry was performed in rat IAs and in human ruptured and unruptured IAs from patients enrolled in the @neurIST observational cohort. An increased frequency of fatal aortic dissection was unexpectedly observed in PCK rats, which was due to modifications in the elastic architecture of the aorta in combination with the induced hypertension. Interestingly, IAs developed faster in PCK rats compared to WT rats. Variations in the anatomy of the circle of Willis were identified in PCK rats and PKD patients, a risk factor that may (in part) explain the higher IA incidence found in these groups. At 2-weeks after induction, the endothelium of IAs from PCK rats showed a decrease in the tight junction proteins zonula occludens-1 and claudin-5. Furthermore, the type III collagen content was lower in IAs of PCK rats at 4-weeks post-surgery. The decrease in tight junction proteins was also observed in the endothelium of human ruptured IAs compared to unruptured IAs. Conclusions Our study showed that PCK rats are more sensitive to IA induction. Variations in the anatomy of the circle of Willis and impaired regulation of tight junction proteins might put PCK rats and PKD patients more at risk of developing vulnerable IAs.