Detailed characterization of cardiac function and structure in 6-month-old female and male PKD/Mhm (Cy/+) rats

Background: Polycystic kidney disease (PKD) is a genetic disorder that leads to renal dysfunction and ultimately progresses to end-stage renal failure. In patients with autosomal dominant polycystic kidney disease (ADPKD), cardiovascular abnormalities are the leading cause of morbidity and mortality. Our study aimed to investigate the impact of ADPKD on cardiac function and structure in both female and male PKD rats.

Method: Six-month-old heterozygous PKD/Mhm (Cy/+) male (n=10; 438±7g) and age-matched non-affected homozygous (+/+) male control (n=10; 425±6g) rats, as well as PKD-female (n=10; 292±5g) and control-female (n=10; 288±4g) rats were anesthetized and in vivo left-ventricular (LV) cardiac function was assessed. Biomarkers of renal function were evaluated and histology was performed.

Results: Serum urea and creatinine levels were increased only in the PKD males compared to their controls (urea 13287±1538 vs. 4685±172 µM, creatinine 103±13 vs. 34±3 µM, p<0.05). In both female and male rats, the serum albumin level was decreased and potassium levels were increased compared to their respective controls (albumin: PKD-female 29.2±0.9 vs. control-female 31.7±0.8 g/L; PKD-male 27.3±0.6 vs. control-male 31.3±0.5 g/L, potassium: PKD-female 5.4±0.4 vs. control-female 4.5±0.1 mM; PKD-male 5.6±0.2 vs. control-male 4.5±0.2 mM, p<0.05). Recordings of the arterial blood pressure showed that compared to controls, PKD-male rats exhibited increased systolic blood pressure (188±9 vs. 140±3 mmHg, p<0.05), diastolic blood pressure (141±5 vs. 112±2 mmHg, p<0.05), mean arterial pressure (157±6 vs. 121±2 mmHg, p<0.05), while the heart rate remained unchanged. Furthermore, LV end-systolic and end-diastolic pressures were higher in the PKD-males than in the controls. Although there was no significant difference in body weight, the heart-to-body weight ratio was increased in the PKD-males compared to controls (0.00366 ± 0.00012 vs. 0.00289 ± 0.00004 g/kg, p<0.05). Consistent with this, histological examination revealed cardiomyocyte hypertrophy. Additionally, compared to controls, PKD-male rats exhibited increased systolic performance in the presence of diastolic dysfunction and higher energy consumption. All these parameters were unchanged in PKD-females compared to their controls.

Conclusion: Male PKD rats can serve as a model for identifying potential therapeutics to mitigate the cardiovascular complications associated with ADPKD.