Background: The risk of cardiovascular events rises after AKI. Leukocytes promote atherosclerotic plaque growth and instability. We established a model of enhanced remote atherosclerosis after renal ischemia-reperfusion (IR) injury and investigated the underlying inflammatory mechanisms.
Methods: Atherosclerotic lesions and inflammation were investigated in native and bone marrow-transplanted LDL receptor-deficient (LDLr-/- ) mice after unilateral renal IR injury using histology, flow cytometry, and gene expression analysis.
Results: Aortic root atherosclerotic lesions were significantly larger after renal IR injury than in controls. A gene expression screen revealed enrichment for chemokines and their cognate receptors in aortas of IR-injured mice in early atherosclerosis, and of T cell-associated genes in advanced disease. Confocal microscopy revealed increased aortic macrophage proximity to T cells. Differential aortic inflammatory gene regulation in IR-injured mice largely paralleled the pattern in the injured kidney. Single-cell analysis identified renal cell types that produced soluble mediators upregulated in the atherosclerotic aorta. The analysis revealed a marked early increase in Ccl2, which CCR2+ myeloid cells mainly expressed. CCR2 mediated myeloid cell homing to the post-ischemic kidney in a cell-individual manner. Reconstitution with Ccr2-/- bone marrow dampened renal post-ischemic inflammation, reduced aortic Ccl2 and inflammatory macrophage marker CD11c, and abrogated excess aortic atherosclerotic plaque formation after renal IR.
Conclusions: Our data introduce an experimental model of remote proatherogenic effects of renal IR and delineate myeloid CCR2 signaling as a mechanistic requirement. Monocytes should be considered as mobile mediators when addressing systemic vascular sequelae of kidney injury.
Keywords: acute kidney injury; arteriosclerosis; cardiovascular disease; chronic inflammation; macrophages; renal ischemia.
Copyright © 2022 by the American Society of Nephrology.