Open Access

Renin-angiotensin system activation accelerates atherosclerosis in experimental renal failure by promoting endoplasmic reticulum stress-related inflammation

  • Authors:
    • Jia Yang
    • Xi Zhang
    • Xinyi Yu
    • Weixue Tang
    • Hua Gan
  • View Affiliations

  • Published online on: January 12, 2017     https://doi.org/10.3892/ijmm.2017.2856
  • Pages: 613-621
  • Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

In this study, we investigated the association between the renin-angiotensin system (RAS), endoplasmic reticulum (ER) stress and atherosclerosis (AS) in uremic apolipoprotein E knockout (apoE-/-) mice. Mild uremia was induced by a 5/6 nephrectomy (5/6 Nx) in 10-week-old apoE-/- mice. Four weeks after nephrectomy, the mice received losartan or no treatment for 16 weeks. Sham-operated mice served as the controls. We found that uremia accelerated AS at the aortic root. The activation of ER stress and the significant upregulation of pro-inflammatory cytokines and chemokines were observed in the uremic mice. Phosphorylated inositol-requiring 1α (p-IRE1α), an ER stress marker protein, was mainly expressed in macrophages in the atherosclerotic lesions. Treatment with losartan significantly attenuated aortic AS, inhibited ER stress and reduced aortic inflammation. In in vitro experiments, angiotensin II (Ang II) increased the levels of the common ER stress maker, glucose-regulated protein 78 (GRP78) and the phosphorylation of IRE1α in RAW264.7 macrophages. Treatment with losartan inhibited the activation of ER stress and the upregulation of GRP78, and enhanced the expression of nuclear factor-κB (NF-κB) inhibitor (IκB) in Ang II-stimulated RAW264.7 macrophages. IRE1α‑siRNA suppressed inflammation and downregulated IκB expression and IκB kinase (IKK) phosphorylation, which inhibited IκB degradation and NF-κB p65 nuclear translocation in Ang II-treated RAW264.7 macrophages. These findings suggest that RAS activation accelerates AS by promoting ER stress-related inflammation in uremic mice.
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March-2017
Volume 39 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Copy and paste a formatted citation
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Spandidos Publications style
Yang J, Zhang X, Yu X, Tang W and Gan H: Renin-angiotensin system activation accelerates atherosclerosis in experimental renal failure by promoting endoplasmic reticulum stress-related inflammation. Int J Mol Med 39: 613-621, 2017
APA
Yang, J., Zhang, X., Yu, X., Tang, W., & Gan, H. (2017). Renin-angiotensin system activation accelerates atherosclerosis in experimental renal failure by promoting endoplasmic reticulum stress-related inflammation. International Journal of Molecular Medicine, 39, 613-621. https://doi.org/10.3892/ijmm.2017.2856
MLA
Yang, J., Zhang, X., Yu, X., Tang, W., Gan, H."Renin-angiotensin system activation accelerates atherosclerosis in experimental renal failure by promoting endoplasmic reticulum stress-related inflammation". International Journal of Molecular Medicine 39.3 (2017): 613-621.
Chicago
Yang, J., Zhang, X., Yu, X., Tang, W., Gan, H."Renin-angiotensin system activation accelerates atherosclerosis in experimental renal failure by promoting endoplasmic reticulum stress-related inflammation". International Journal of Molecular Medicine 39, no. 3 (2017): 613-621. https://doi.org/10.3892/ijmm.2017.2856