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Atherosclerosis in chronic kidney disease: the role of macrophages

Nature Reviews Nephrology volume 7, pages 45–54 (2011)Cite this article

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Abstract

Patients with chronic kidney disease (CKD) are at increased risk of atherosclerotic cardiovascular disease and loss of renal parenchyma accelerates atherosclerosis in animal models. Macrophages are central to atherogenesis because they regulate cholesterol traffic and inflammation in the arterial wall. CKD influences macrophage behavior at multiple levels, rendering them proatherogenic. Even at normal creatinine levels, macrophages from uninephrectomized Apoe−/− mice are enriched in cholesterol owing to downregulation of cholesterol transporter ATP-binding cassette subfamily A member 1 levels and activation of nuclear factor κB, which leads to impaired cholesterol efflux. Interestingly, treatment with an angiotensin-II-receptor blocker (ARB) improves these effects. Moreover, atherosclerotic aortas from Apoe−/− mice transplanted into renal-ablated normocholesterolemic recipients show plaque progression and increased macrophage content instead of the substantial regression seen in recipient mice with intact kidneys. ARBs reduce atherosclerosis development in mice with partial renal ablation. These results, combined with the clinical benefits of angiotensin-converting-enzyme (ACE) inhibitors and ARBs in patients with CKD, suggest an important role for the angiotensin system in the enhanced susceptibility to atherosclerosis seen across the spectrum of CKD. The role of macrophages could explain why these therapies may be effective in end-stage renal disease, one of the few conditions in which statins show no clinical benefit.

Key Points

  • Even subtle chronic kidney disease (CKD) increases the risk of cardiovascular events in humans and worsens atherosclerosis in experimental models

  • CKD-associated inflammatory and oxidant stress promotes the infiltration and trapping of circulating monocytes in the arterial intima

  • CKD promotes the formation of foam cells by downregulating cholesterol efflux through activation of nuclear factor κB and repression of cholesterol transporter ATP-binding cassette subfamily A member 1

  • CKD modifies lipoproteins and makes them more susceptible to scavenging by macrophages and less capable of acting as acceptors of cellular cholesterol

  • Systemic and macrophage angiotensin II actions contribute to the enhanced susceptibility of patients with CKD to atherosclerosis

  • Treatment with antagonists and inhibitors of angiotensin II might be of particular value in the prevention of cardiovascular disease in patients with CKD

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Figure 1: Potential pathways by which CKD modulates the accumulation of arterial macrophages.
Figure 2: Potential mechanisms by which CKD modulates macrophage lipid handling.

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Acknowledgements

The authors' work described in this Review was supported in part by grants from NIH HL087061 (V. Kon) and DK044757 (V. Kon and S. Fazio), HL086988 and HL065405 (M. F. Linton), HL65709 and HL57986 (S. Fazio), and the Lipid, Lipoprotein and Atherosclerosis Core of the Vanderbilt Mouse Metabolic Phenotyping Center (NIH DK59637-01).

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  1. Department of Pediatrics, Vanderbilt University Medical Center, 383 Preston Research Building, 2220 Pierce Avenue, Nashville, 37332-6300, TN, USA

    Valentina Kon

  2. Department of Medicine, Vanderbilt University Medical Center, 383 Preston Research Building, 2220 Pierce Avenue, Nashville, 37332-6300, TN, USA

    MacRae F. Linton & Sergio Fazio

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V. Kon, M. F. Linton and S. Fazio contributed equally to all aspects of this manuscript.

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Correspondence to Sergio Fazio.

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Kon, V., Linton, M. & Fazio, S. Atherosclerosis in chronic kidney disease: the role of macrophages. Nat Rev Nephrol 7, 45–54 (2011). https://doi.org/10.1038/nrneph.2010.157

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