Article ; Online: Renin-angiotensin system activation accelerates atherosclerosis in experimental renal failure by promoting endoplasmic reticulum stress-related inflammation.
International journal of molecular medicine
2017 Volume 39, Issue 3, Page(s) 613–621
Abstract: ... macrophages. These findings suggest that RAS activation accelerates AS by promoting ER stress-related ... endoplasmic reticulum (ER) stress and atherosclerosis (AS) in uremic apolipoprotein E knockout (apoE-/-) mice. Mild ... reduced aortic inflammation. In in vitro experiments, angiotensin II (Ang II) increased the levels ...
| 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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| MeSH term(s) | Angiotensin II Type 1 Receptor Blockers/pharmacology ; Animals ; Apolipoproteins E/deficiency ; Atherosclerosis/drug therapy ; Atherosclerosis/etiology ; Atherosclerosis/metabolism ; Biomarkers ; Cell Line ; Disease Models, Animal ; Endoplasmic Reticulum Stress/drug effects ; Endoribonucleases/genetics ; Endoribonucleases/metabolism ; Inflammation/drug therapy ; Inflammation/metabolism ; Losartan/pharmacology ; Macrophages/drug effects ; Macrophages/metabolism ; Male ; Mice ; Mice, Knockout ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; RNA Interference ; Renal Insufficiency/drug therapy ; Renal Insufficiency/etiology ; Renal Insufficiency/metabolism ; Renin-Angiotensin System/drug effects |
| Chemical Substances | Angiotensin II Type 1 Receptor Blockers ; Apolipoproteins E ; Biomarkers ; ERN1 protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Endoribonucleases (EC 3.1.-) ; Losartan (JMS50MPO89) |
| Language | English |
| Publishing date | 2017-03 |
| Publishing country | Greece |
| Document type | Journal Article |
| ZDB-ID | 1444428-8 |
| ISSN | 1791-244X ; 1107-3756 |
| ISSN (online) | 1791-244X |
| ISSN | 1107-3756 |
| DOI | 10.3892/ijmm.2017.2856 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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