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Publication
Atherosclerosis following renal injury is ameliorated by pioglitazone and
losartan via macrophage phenotype.
Authors Yamamoto S, Zhong J, Yancey PG, Zuo Y, Linton MF, Fazio S, Yang H, Narita I, Kon
V
Submitted By Submitted Externally on 11/3/2015
Status Published
Journal Atherosclerosis
Year 2015
Date Published 9/1/2015
Volume : Pages 242 : 56 - 64
PubMed Reference 26184694
Abstract Chronic kidney disease (CKD) amplifies atherosclerosis, which involves
renin-angiotensin system (RAS) regulation of macrophages. RAS influences
peroxisome proliferator-activated receptor-? (PPAR?), a modulator of atherogenic
functions of macrophages, however, little is known about its effects in CKD. We
examined the impact of combined therapy with a PPAR? agonist and angiotensin
receptor blocker on atherogenesis in a murine uninephrectomy model.,
Apolipoprotein E knockout mice underwent uninephrectomy (UNx) and treatment with
pioglitazone (UNx + Pio), losartan (UNx + Los), or both (UNx + Pio/Los) for 10
weeks. Extent and characteristics of atherosclerotic lesions and macrophage
phenotypes were assessed; RAW264.7 and primary peritoneal mouse cells were used
to examine pioglitazone and losartan effects on macrophage phenotype and
inflammatory response., UNx significantly increased atherosclerosis.
Pioglitazone and losartan each significantly reduced the atherosclerotic burden
by 29.6% and 33.5%, respectively; although the benefit was dramatically
augmented by combination treatment which lessened atherosclerosis by 55.7%.
Assessment of plaques revealed significantly greater macrophage area in UNx +
Pio/Los (80.7 ± 11.4% vs. 50.3 ± 4.2% in UNx + Pio and 57.2 ± 6.5% in UNx + Los)
with more apoptotic cells. The expanded macrophage-rich lesions of UNx + Pio/Los
had more alternatively activated, Ym-1 and arginine 1-positive M2 phenotypes
(Ym-1: 33.6 ± 8.2%, p < 0.05 vs. 12.0 ± 1.1% in UNx; arginase 1: 27.8 ± 0.9%, p
< 0.05 vs. 11.8 ± 1.3% in UNx). In vitro, pioglitazone alone and together with
losartan was more effective than losartan alone in dampening
lipopolysaccharide-induced cytokine production, suppressing M1 phenotypic change
while enhancing M2 phenotypic change., Combination of pioglitazone and losartan
is more effective in reducing renal injury-induced atherosclerosis than either
treatment alone. This benefit reflects mitigation in macrophage cytokine
production, enhanced apoptosis, and a shift toward an anti-inflammatory
phenotype.




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