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Abstract: FR-PO136

CKD Mediates Cardiac Dysfunction by Recruiting Monocyte Derived Inflammatory Macrophages

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Woollard, Kevin, Imperial College London, London, United Kingdom
  • Garcia Diaz, Ana Isabel, Imperial College London, London, United Kingdom
  • Tomlinson, James Alexander, Imperial College London, London, United Kingdom
  • Pusey, Charles D., Imperial College London, London, United Kingdom
Background

The relationship between chronic kidney disease (CKD) and accelerated cardiac disease is complex and not fully explained by traditional cardiovascular risk factors. Macrophages have critical roles in both kidney and cardiovascular disease, however a mechanistic link is not well described.

Methods

Using the folate induced nephropathy and 5/6 nephrectomy mouse models of CKD, we show that monocyte derived macrophages infiltrate heart tissue in large numbers but not other organs.

Results

We show using monocyte/macrophage transgenic reporters, with flow cytometry, imaging and qPCR, that the cardiac macrophage pool switches phenotype to a pro-inflammatory state during CKD. This cellular infiltrate was associated with an increase in cardiac remodeling through changes in extracellular matrix gene expression, cardiomyocyte enlargement and decrease in cardiac function, as shown by reduced ejection fraction. This phenotype was rescued by global knockout of C-C chemokine receptor type 2 (CCR2-/-), associated with monocytopenia, during folate nephropathy. Measurement of specific chemokine expression in heart and plasma identified a unique chemokine axis, involving overexpression of CXCL10 that was also present in the plasma of CKD patients.

Conclusion

This work uncovers a novel pathway via CXCL10 that mediates cardiac inflammatory monocyte derived macrophage infiltration in the context of CKD, thus identifying new biological targets for improved diagnosis, prognosis and treatment of cardiomyopathy risk in CKD patients.