Sex-specific cardiac dysfunction in mice with chronic kidney disease

Area of Science:

• Nephrology
• Cardiology
• Toxicology

Background:

• Cardiovascular disease (CVD) is a primary cause of mortality in chronic kidney disease (CKD) patients.
• Rodent models are crucial for investigating the mechanisms of uremic CVD.
• This study compares cardiac function in male and female mice across two established CKD models.

Purpose of the Study:

• To compare cardiac function parameters in male and female mice with CKD.
• To investigate the association between gut-derived uremic toxins and echocardiographic findings in CKD.
• To identify sex-based differences in cardiac response to CKD and uremic toxins.

Main Methods:

• Two mouse models of CKD (adenine-induced and 5/6 nephrectomy) were used, including male and female C57Bl/6J mice.
• Echocardiography was performed at 17 weeks to assess cardiac function.
• Serum markers of kidney dysfunction, gut-derived uremic toxins, and left ventricle gene expression were analyzed.

Main Results:

• Both CKD models showed elevated kidney dysfunction markers and increased indoxyl sulfate. Trimethylamine N-oxide and p-cresyl sulfate levels varied by model.
• Male CKD mice exhibited decreased cardiac output and ejection fraction. Female CKD mice showed preserved cardiac function compared to female controls.
• Gut toxins (trimethylamine N-oxide, indoxyl sulfate) correlated with reduced cardiac output in males. Transcriptomics revealed sex-specific variations in cardiac pathways.

Conclusions:

• Significant sex differences exist in cardiac function and serum profiles within preclinical CKD models.
• Gut-derived uremic toxins may contribute to cardiorenal pathophysiology and impaired cardiac output in male CKD.
• These findings underscore the importance of considering sex in CKD-related cardiovascular research.