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

M A Mawhin,E I Vloumidi,A Sardini,J D Fourre,J Tomlinson,C D Pusey,R G Bright,K J Woollard

doi:10.1186/s12882-021-02593-7

Abstract

BackgroundThe leading cause of death in end-stage kidney disease is related to cardiovascular disease. Macrophages are known to be involved in both chronic kidney disease (CKD) and heart failure, however their role in the development of cardiorenal syndrome is less clear. We thus sought to investigate the role of macrophages in uremic cardiac disease.MethodsWe assessed cardiac response in two experimental models of CKD and tested macrophage and chemokine implication in monocytopenic CCR2−/− and anti-CXCL10 treated mice. We quantified CXCL10 in human CKD plasma and tested the response of human iPSC-derived cardiomyocytes and primary cardiac fibroblasts to serum from CKD donors.ResultsWe found that reduced kidney function resulted in the expansion of cardiac macrophages, in particular through local proliferation of resident populations. Influx of circulating monocytes contributed to this increase. We identified CXCL10 as a crucial factor for cardiac macrophage expansion in uremic disease. In humans, we found increased plasma CXCL10 concentrations in advanced CKD, and identified the production of CXCL10 in cardiomyocytes and cardiac fibroblasts.ConclusionsThis study provides new insight into the role of the innate immune system in uremic cardiomyopathy.

Highlights

More than 50% of deaths are attributable to cardiovascular diseases (CVD) [1,2,3]
Immune responses are thought to be integral to chronic kidney disease (CKD), considered to be a prototypical example of inflammatory disease [8], and the increased risk of CVD is perhaps unsurprisingly linked to immune cells, as shown for T cells in models of uremic cardiomyopathy [4, 14, 18,19,20]
Experimental CKD induced by 5/6 nephrectomy induces cardiomyopathy Renal impairment by 5/6 Nx (Fig. 1A) resulted in significant increases in plasma markers of CKD at 12 weeks: symmetric dimethylarginine (SDMA), blood urea nitrogen (BUN), and creatinine (Fig. 1B)

Summary

Introduction

More than 50% of deaths are attributable to cardiovascular diseases (CVD) [1,2,3]. Even mild chronic kidney disease (CKD) with isolated albuminuria has been associated with a 2- to 4-fold increased risk of cardiovascular events [1]. Macrophages have been shown to be important in all stages of inflammatory and fibrotic kidney disease [11] Their role in cardiovascular comorbidity with kidney disease is less well described, but macrophage activation regulates immune responses during cardiac stress as well as promoting diastolic dysfunction in hypertension and pressure overload models [12,13,14,15,16,17]. Immune responses are thought to be integral to CKD, considered to be a prototypical example of inflammatory disease [8], and the increased risk of CVD is perhaps unsurprisingly linked to immune cells, as shown for T cells in models of uremic cardiomyopathy [4, 14, 18,19,20]. Macrophages are known to be involved in both chronic kidney disease (CKD) and heart failure, their role in the development of cardiorenal syndrome is less clear. We sought to investigate the role of macrophages in uremic cardiac disease

Methods

Results

Discussion

Conclusion