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Basic ResearchImmunology and Pathology
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Myeloid CCR2 Promotes Atherosclerosis after AKI

Anne M. Hüsing, Vera C. Wulfmeyer, Svenja Gaedcke, Susanne V. Fleig, Song Rong, David DeLuca, Hermann Haller, Roland Schmitt and Sibylle von Vietinghoff
JASN June 2022, ASN.2022010048; DOI: https://doi.org/10.1681/ASN.2022010048
Anne M. Hüsing
1Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
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Vera C. Wulfmeyer
1Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
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Svenja Gaedcke
2German Centre for Lung Research, Hannover Medical School, Hannover, Germany
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Susanne V. Fleig
1Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
3Nephrology Section, Medical Clinic 1, University Hospital Bonn, Rheinische Friedrich Wilhelm University of Bonn, Bonn, Germany
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Song Rong
1Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
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David DeLuca
2German Centre for Lung Research, Hannover Medical School, Hannover, Germany
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Hermann Haller
1Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
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Roland Schmitt
1Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
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Sibylle von Vietinghoff
1Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
3Nephrology Section, Medical Clinic 1, University Hospital Bonn, Rheinische Friedrich Wilhelm University of Bonn, Bonn, Germany
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Significance Statement

AKI impairs excretory function, but also leaves a damaged kidney. We demonstrate that a single episode of unilateral ischemia-reperfusion injury significantly promotes atherosclerotic plaque formation in mice. Renal inflammation preceded expression of myeloid and T-cell genes in the atherosclerotic aorta. The chemokine receptor CCR2 was instrumental in inflammatory monocyte recruitment to the kidney, renal and aortic inflammatory macrophage marker CD11c expression, and enhanced aortic plaque formation after AKI. Delineating underlying mechanisms in atherosclerosis support the concept of a “toxic kidney” that promotes remote inflammation after ischemic reperfusion injury.

Abstract

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.

  • arteriosclerosis
  • cardiovascular disease
  • chronic inflammation
  • renal ischemia
  • macrophages
  • acute kidney injury
  • Copyright © 2022 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 33 (6)
Journal of the American Society of Nephrology
Vol. 33, Issue 6
June 2022
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Myeloid CCR2 Promotes Atherosclerosis after AKI
Anne M. Hüsing, Vera C. Wulfmeyer, Svenja Gaedcke, Susanne V. Fleig, Song Rong, David DeLuca, Hermann Haller, Roland Schmitt, Sibylle von Vietinghoff
JASN Jun 2022, ASN.2022010048; DOI: 10.1681/ASN.2022010048

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Myeloid CCR2 Promotes Atherosclerosis after AKI
Anne M. Hüsing, Vera C. Wulfmeyer, Svenja Gaedcke, Susanne V. Fleig, Song Rong, David DeLuca, Hermann Haller, Roland Schmitt, Sibylle von Vietinghoff
JASN Jun 2022, ASN.2022010048; DOI: 10.1681/ASN.2022010048
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Keywords

  • arteriosclerosis
  • cardiovascular disease
  • chronic inflammation
  • renal ischemia
  • macrophages
  • acute kidney injury

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