C-C motif receptor 2 is a core profibrotic factor in uremic cardiomyopathy

Area of Science:

• Cardiovascular Medicine
• Nephrology
• Molecular Biology

Background:

• Uremic cardiomyopathy (UC) is a major cause of death in chronic kidney disease (CKD).
• The mechanisms driving UC, including left ventricular hypertrophy (LVH) and fibrosis, are not fully understood.
• Novel animal models are crucial for studying UC pathogenesis.

Purpose of the Study:

• To develop and compare novel rodent models of UC.
• To investigate the molecular mechanisms underlying UC.
• To identify and validate new therapeutic targets for UC.

Main Methods:

• Development of modified nephrectomy (MNx) and adenine-normal diet models for UC simulation.
• Transcriptomic analysis of left ventricular (LV) tissues from UC models.
• Evaluation of C-C-motif receptor 2 (CCR-2) blockade effects on cardiac fibrosis and LVH.

Main Results:

• Transcriptomic analysis revealed global molecular changes in UC, including cell cycle dysregulation, ECM remodeling, and metabolic alterations.
• Distinct molecular profiles were observed between MNx- and adenine-induced UC models.
• CCR-2 blockade significantly reduced cardiac fibrosis without impacting LVH.
• CCR-2 inhibition promoted cardiac residual macrophage expansion, mediating antifibrotic effects.

Conclusions:

• CCR-2 plays a critical role in the development of cardiac fibrosis in UC.
• CCR-2 inhibition represents a promising therapeutic strategy for mitigating fibrosis in UC.
• Understanding UC pathogenesis through novel models advances potential treatments for CKD patients.