Chronic kidney disease mediates cardiac dysfunction associated with increased resident cardiac macrophages

Area of Science:

• Immunology
• Cardiovascular Medicine
• Nephrology

Background:

• Cardiovascular disease is the primary cause of death in end-stage kidney disease.
• Macrophages are implicated in chronic kidney disease (CKD) and heart failure, but their role in cardiorenal syndrome is unclear.
• This study investigates the role of macrophages in uremic cardiac disease.

Purpose of the Study:

• To elucidate the role of macrophages in the development of uremic cardiomyopathy.
• To identify key molecular mechanisms driving cardiac macrophage accumulation in CKD.
• To explore the translational relevance of these findings in human CKD patients.

Main Methods:

• Utilized two experimental models of CKD to assess cardiac response.
• Investigated macrophage and chemokine involvement using monocytopenic CCR2-/- mice and anti-CXCL10 treatment.
• Quantified CXCL10 in human CKD plasma and assessed responses of human iPSC-derived cardiomyocytes and cardiac fibroblasts to CKD serum.

Main Results:

• Reduced kidney function led to cardiac macrophage expansion, primarily via local proliferation.
• Circulating monocyte influx also contributed to increased cardiac macrophages.
• CXCL10 was identified as a critical factor for cardiac macrophage expansion in uremic disease.
• Elevated plasma CXCL10 concentrations were observed in advanced human CKD.
• Cardiomyocytes and cardiac fibroblasts were identified as sources of CXCL10 in humans.

Conclusions:

• This research provides novel insights into the innate immune system's function in uremic cardiomyopathy.
• CXCL10 signaling is a key pathway mediating cardiac macrophage accumulation in CKD.
• Findings highlight potential therapeutic targets for managing cardiorenal syndrome.