The relationship between chronic kidney disease (CKD) and increasing rates of cardiovascular disease and mortality is complex, but is important due to the massive increased risk of cardiovascular events noted in CKD patients. Macrophages have critical roles in kidney and cardiovascular disease. However, since a deeper understanding of macrophage ontogeny and heterogeneity, we wanted to revisit the role of cardiovascular macrophages during CKD.
Using the folate induced nephropathy and 5/6 nephrectomy mouse models of CKD, we have new exciting data showing that during CKD, independent of atherosclerosis, inflammatory macrophages are infiltrating cardiac tissue. Using flow cytometry, RNA profiling, histology and ultrasound, we analysed the phenotype and function of the heart and immune cell infiltrate during CKD.
After 12 weeks of CKD, CD11bposF480posCD169neg monocyte derived macrophages infiltrate heart tissue in large numbers. This is only evident in cardiovascular tissue, with no systemic infiltrate in lungs, spleen, kidney or liver. Interestingly, we also noted an increase in cardiac CD19pos B-cell and Gr1pos neutrophil infiltrate over the course of CKD. The cellular infiltrate was associated with an increase in cardiac fibrosis markers and decrease in heart function, as shown by decreased ejection fraction. Measuring specific chemokine expression in heart and plasma identified a unique chemokine axis, which may be regulating macrophage and other immune cell recruitment to heart tissue during CKD. Moreover, we confirmed the ontogeny of these cardiac macrophages through Ly6Chigh monocyte lineages using CCR2 deficient mice, which improved cardiac function.
This work uncovers a unique pathway that mediates inflammatory monocyte derived macrophage infiltration in the heart during CKD. More work is now being performed to confirm mechanisms and cardiovascular phenotype in our CKD models. Ultimately these studies may identify new therapeutic targets for CKD patients, to reduce their cardiovascular risk.
- Chronic Kidney Disease
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