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Kidney Week

Abstract: SA-PO112

AKI Enhances Aortic Plaque Formation in a Mouse Model of Atherosclerosis in a CCR2-Dependent Manner

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Breloh, Anne M., Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
  • Wulfmeyer, Vera Christine, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
  • Gaedcke, Svenja, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
  • Fleig, Susanne V., Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
  • Rong, Song, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
  • Deluca, David S., Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
  • Haller, Hermann G., Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
  • Schmitt, Roland, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany
  • Von Vietinghoff, Sibylle, Universitatsklinikum Bonn, Bonn, Nordrhein-Westfalen, Germany
Background

Acute kidney injury enhances the risk of subsequent cardiovascular events. To determine underlying mechanisms, we established a model of atherosclerosis after renal ischemia reperfusion (IR) injury. Leukocytes promote atherosclerotic plaque growth and instability. We here studied underlying recruitment mechanisms.

Methods

Atherosclerotic lesions and inflammation were investigated in native and bone marrow-transplanted LDL receptor deficient (LDLr-/-) mice after unilateral renal IR injury by histology, flow cytometry and gene expression analysis.

Results

Aortic root atherosclerotic lesion size was significantly larger after renal IR than in controls. A gene expression screen revealed enrichment of chemokines and their cognate receptors in aortas of IR mice in early atherosclerosis. In advanced disease, this was complemented by T cell-associated genes. Increased aortic macrophage proximity to T cells was observed by confocal microscopy. Differential aortic inflammatory gene regulation in IR mice largely paralleled the pattern in the injured kidney. Renal cell types that produced soluble mediators upregulated in the atherosclerotic aorta were identified by single cell analysis. It revealed a marked early increase in Ccl2, which was mainly expressed by CCR2+ myeloid cells. 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, and abrogated excess aortic atherosclerotic plaque formation after renal IR. Ablation of CCR2 significantly altered the inflammatory gene expression profile in the atherosclerotic aortas after renal IR.

Conclusion

Our data introduce an experimental model of remote proatherogenic effects of renal IR and delineate myeloid CCR2 signaling as a mechanistic requirement. Further investigations will need to address regulation of aortic gene expression and monocytes as mobile mediators of vascular sequelae after kidney injury.