title: Renin-angiotensin system activation accelerates atherosclerosis in experimental renal failure by promoting endoplasmic reticulum stress-related inflammation.
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.
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Yu
authors.affiliation: Experimental Study Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Weixue
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Gan
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D015415:Biomarkers; D002460:Cell Line; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051437:Renal Insufficiency / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D019808:Losartan