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J Am Soc Nephrol. 2014 Jun;25(6):1198-209. doi: 10.1681/ASN.2013050542. Epub 2014 Feb 7.

Angiopoietin-2-induced arterial stiffness in CKD.

Author information

1
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan; Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Chu-Tung Branch, Hsin-Chu, Taiwan; and.
2
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;
3
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
4
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan; Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
5
Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
6
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan; Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;
7
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan; Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; linsl@ntu.edu.tw.

Abstract

The mechanism of vascular calcification in CKD is not understood fully, but may involve collagen deposition in the arterial wall upon osteo/chondrocytic transformation of vascular smooth muscle cells (VSMCs). Increased levels of circulating angiopoietin-2 correlate with markers of CKD progression and angiopoietin-2 regulate inflammatory responses, including intercellular and vascular adhesion and recruitment of VSMCs. Here, we investigate the potential role of angiopoietin-2 in the pathogenesis of arterial stiffness associated with CKD. In a cohort of 416 patients with CKD, the plasma level of angiopoietin-2 correlated independently with the severity of arterial stiffness assessed by pulse wave velocity. In mice subjected to 5/6 subtotal nephrectomy or unilateral ureteral obstruction, plasma levels of angiopoietin-2 also increased. Angiopoietin-2 expression markedly increased in tubular epithelial cells of fibrotic kidneys but decreased in other tissues, including aorta and lung, after 5/6 subtotal nephrectomy. Expression of collagen and profibrotic genes in aortic VSMCs increased in mice after 5/6 subtotal nephrectomy and in mice producing human angiopoietin-2. Angiopoietin-2 stimulated endothelial expression of chemokines and adhesion molecules for monocytes, increased Ly6C(low) macrophages in aorta, and increased the expression of the profibrotic cytokine TGF-β1 in aortic endothelial cells and Ly6C(low) macrophages. Angiopoietin-2 blockade attenuated expression of monocyte chemokines, profibrotic cytokines, and collagen in aorta of mice after 5/6 subtotal nephrectomy. This study identifies angiopoietin-2 as a link between kidney fibrosis and arterial stiffness. Targeting angiopoietin-2 to attenuate inflammation and collagen expression may provide a novel therapy for cardiovascular disease in CKD.

PMID:
24511140
PMCID:
PMC4033368
DOI:
10.1681/ASN.2013050542
[Indexed for MEDLINE]
Free PMC Article
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