#3357 MORPHOMETRIC AND FUNCTIONAL EVALUATION OF A NON-RENAL VASCULATURE IN FEMALE AND MALE PKD/MHM (CY/+) RATS

Abstract Background and Aims Polycystic kidney disease (PKD) is a cystic genetic disorder of the kidneys. Vascular abnormalities are the most important non-cystic complications in PKD. In the present study, we evaluated aortic morphometry and vascular function in female and male PKD/Mhm (Cy/+) rats, an animal model of autosomal dominant PKD. Method Thoracic aortic rings from six month-old heterozygous PKD/Mhm (Cy/+) female (n = 10; 307±4g) and male (n = 10; 470±24g) and age-matched non-affected homozygous (+/+) Control-female (n = 9; 312±6g) and Control-male (n = 13; 460±14g) rats were used a) to evaluate both contractile/relaxation responses ex vivo using organ bath experiments and b) to study aortic morphometry assessed by hematoxylin&eosin staining. Furthermore, immunohistochemistry for cleaved poly (ADP-ribose) polymerase (PARP)-1 was performed. Results Although there was no significant difference in body weight, serum creatinine levels were increased in the PKD-female and PKD-male rats compared with the respective controls (PKD-female 50.0±1.7 vs. Control-female 43.9±2.1 µmol/L; PKD-male 178.7±21.0 vs. Control-male 40.4± 1.3 µmol/L, p<0.05) and were found to be higher in PKD-male rats than in the PKD-females (p<0.0001). Compared to Control-male, PKD-male rats showed decreased maximum relaxation to acetylcholine (55±2% vs. 77±1%, p<0.05), indicating impaired endothelial function. Contractile responses to phenylephrine (3.0±0.1g vs. 3.4±0.1g, p<0.05) and high potassium (3.3±0.1g vs. 3.7±0.1g, p<0.05) were reduced in the PKD-male compared to Control-male. Additionally, in PKD-male aortas, the concentration-response curve to sodium nitroprusside, an endothelium-independent vasodilator, was shifted to the right compared to Control-male. Morphometrical analysis revealed that wall thickness and wall cross-sectional area normalized to body weight, and the wall:lumen area ratio were significantly higher in PKD-male aortas compared to Control-male. Additionally, PKD-male showed increased cleaved PARP-1 immunoreactivity confined to endothelial level compared to Control-male. All these parameters were unchanged in PKD-female rats compared to Control-female. Conclusion Six month-old PKD-male, not female, rats show endothelial dysfunction, impaired smooth muscle contraction and relaxation, pathological changes in aortic morphometry, and apoptosis in a non-renal vasculature. The rat model of autosomal dominant PKD in males can be used to identify novel targets for the treatment of this disease.