Abstract: FR-PO384
Vascular Dysfunction in the C57Bl/6J;Pkd1RC/RC Mouse Model of Autosomal Dominant Polycystic Kidney Disease Mimics Human Disease
Session Information
- Hypertension and CVD: Basic
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Dwivedi, Nidhi, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Gitomer, Berenice Y., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Edelstein, Charles L., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Chonchol, Michel, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Hopp, Katharina, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Brunt, Vienna E., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic nephropathy characterized by progressive cyst growth in the kidney. Patients with ADPKD also present with cardiovascular diseases (CVDs), a leading cause of morbidity and mortality in this population. The majority of CVDs arise due to dysfunction of the arteries. Stiffening of the large arteries (e.g., aorta and carotids) and endothelial dysfunction are manifestations of vascular dysfunction that precede and contribute to CVDs and are often found in patients with early-stage ADPKD, even when kidney function remains preserved. The C57Bl/6J Pkd1RC/RC (RC/RC) mouse model mimics the kidney phenotype of patients with ADPKD and is widely used to study kidney pathologies of the disease, but it is unknown if the model also exhibits vascular dysfunction.
Methods
Using male RC/RC mice with mild (4mo) and moderate (8mo) kidney disease severity and age/sex matched C57Bl/6J wildtype (WT) controls, we measured aortic stiffness in vivo by pulse wave velocity (PWV). To investigate the contribution of structural changes in the arteries to stiffening, we also measured aortic elastic modulus by stress-strain testing (wire myography) in excised aortic rings. Lastly, we measured endothelial function as endothelium-dependent dilation (EDD) to acetylcholine in isolated carotid arteries by pressure myography.
Results
Aortic PWV was higher in RC/RC mice vs WT at both 4 (440±44 vs 346±26 cm/s, P<0.01) and 8mo (428±37 vs 343±30 cm/s, P<0.01) of age. Aortic elastic modulus trended towards being mildly but non-significantly higher in RC/RC vs WT. Carotid artery EDD was impaired at 8mo (peak EDD: 74±6 vs 97±3%, P<0.01) but not 4mo (93±5 vs 94±2%) of age in RC/RC mice vs WT.
Conclusion
Our data suggest that the RC/RC mouse model of ADPKD presents with vascular dysfunction like that observed in patients with ADPKD. Our vascular data is in line with a prior described cardiac phenotype showing cardiac hypertrophy and echocardiographic changes in the heart in RC/RC mouse (FR-PO279 ASN 2022). Thus, this model can be utilized to study mechanisms and test novel interventions aimed to reduce CVD risk in ADPKD.