Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype. Issue 1 (September 2015)

• Record Type: Journal Article
• Authors: Yamamoto, Suguru; Zhong, Jiayong; Yancey, Patricia G.; Zuo, Yiqin; Linton, MacRae F.; Fazio, Sergio; Yang, Haichun; Narita, Ichiei; Kon, Valentina
• Is Part Of: Atherosclerosis. Volume 242:Issue 1(2015)
• Page Start: 56
• Page End: 64
• Publication Date: 2015-09
• Subjects: Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2015.06.055
• Languages: English
• ISSNs: 0021-9150

Abstract

<abstract xml:lang="en" abstract-type="author" id="abs0010"> <title id="sectitle0010">Abstract</title> <sec> <title id="sectitle0015">Objective</title> <p id="abspara0010">Chronic kidney disease (CKD) amplifies atherosclerosis, which involves renin-angiotensin system (RAS) regulation of macrophages. RAS influences peroxisome proliferator-activated receptor-γ (PPARγ), 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 PPARγ agonist and angiotensin receptor blocker on atherogenesis in a murine uninephrectomy model.</p> </sec> <sec> <title id="sectitle0020">Methods</title> <p id="abspara0015">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.</p> </sec> <sec> <title id="sectitle0025">Results</title> <p id="abspara0020">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% <italic>vs</italic>. 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%, <italic>p</italic> < 0.05 <italic>vs</italic>. 12.0 ± 1.1% in UNx; arginase 1: 27.8 ± 0.9%, <italic>p</italic> < 0.05 <italic>vs</italic>. 11.8 ± 1.3% in UNx). <italic>In vitro</italic>, 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.</p> </sec> <sec> <title id="sectitle0030">Conclusion</title> <p id="abspara0025">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.</p> </sec> </abstract>