Morphometric and functional evaluation of non-renal vasculature in female and male PKD/Mhm (Cy/+) Rats

Background: Polycystic kidney disease (PKD) is a genetic disorder characterized by renal enlargement due to cyst formation. Besides cystic complications, patients with autosomal dominant PKD (ADPKD) can develop vascular abnormalities. We investigated the impact of ADPKD on aortic morphometry and function in female and male PKD rats. Method: Thoracic aortic rings were obtained from six-month-old female (n=10; 307±4g) and male (n=10; 470±24g) PKD/Mhm (Cy/+) rats, as well as age-matched control-female (n=9; 312±6g) and control-male (+/+) (n=13; 460±14g) rats. Vascular function was evaluated ex vivo using organ baths. Biomarkers of renal function were evaluated and histology was performed. Results: PKD-female and PKD-male rats showed elevated serum creatinine levels compared to their respective controls (PKD-female: 50.0±1.7μmol/L vs. control-female: 43.9±2.1μmol/L; PKD-male: 178.7±21.0μmol/L vs. control-male: 40.4±1.3μmol/L, p<0.05), and that in the PKD-males were found to be higher in the PKD-males than in the PKD-females (p<0.0001). Endothelial dysfunction, characterized by reduced maximum relaxation to acetylcholine was observed in the PKD-males compared to control-males (55±2% vs. 77±1%, p<0.05). Additionally, contractile responses to phenylephrine and high potassium were decreased in PKD-male compared to control-male. Morphometric analysis revealed increased wall thickness, wall cross-sectional area normalized to body weight, and wall: lumen area ratio in PKD-male aortas compared to control-male. Additionally, PKD-male showed increased cleaved poly(ADP-Ribose)-polymerase-1 immunoreactivity compared to control-males. All these parameters were unchanged in PKD-females compared to control-females. Conclusion: Six-month-old male rats with PKD, but not females, display endothelial dysfunction, impaired smooth muscle contraction/relaxation, pathological changes in aortic morphometry, and increased apoptosis, providing a model for studying vascular complications in ADPKD.