Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype

Suguru Yamamoto, Jiayong Zhong, Patricia G. Yancey, Yiqin Zuo, MacRae F. Linton, Sergio Fazio, Haichun Yang, Ichiei Narita, Valentina Kon

    Research output: Contribution to journalArticle

    15 Citations (Scopus)

    Abstract

    Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

    Original languageEnglish (US)
    Pages (from-to)56-64
    Number of pages9
    JournalAtherosclerosis
    Volume242
    Issue number1
    DOIs
    StatePublished - Sep 1 2015

    Fingerprint

    pioglitazone
    Losartan
    Atherosclerosis
    Macrophages
    Phenotype
    Kidney
    Wounds and Injuries
    Peroxisome Proliferator-Activated Receptors
    Renin-Angiotensin System
    Chronic Renal Insufficiency
    Cytokines
    Arginase
    Angiotensin Receptor Antagonists
    Apolipoproteins E
    Knockout Mice
    Lipopolysaccharides
    Arginine
    Anti-Inflammatory Agents

    Keywords

    • Atherosclerosis
    • Chronic kidney disease
    • Losartan
    • Macrophage phenotype
    • Pioglitazone
    • PPARγ

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

    Cite this

    Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype. / Yamamoto, Suguru; Zhong, Jiayong; Yancey, Patricia G.; Zuo, Yiqin; Linton, MacRae F.; Fazio, Sergio; Yang, Haichun; Narita, Ichiei; Kon, Valentina.

    In: Atherosclerosis, Vol. 242, No. 1, 01.09.2015, p. 56-64.

    Research output: Contribution to journalArticle

    Yamamoto, Suguru ; Zhong, Jiayong ; Yancey, Patricia G. ; Zuo, Yiqin ; Linton, MacRae F. ; Fazio, Sergio ; Yang, Haichun ; Narita, Ichiei ; Kon, Valentina. / Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype. In: Atherosclerosis. 2015 ; Vol. 242, No. 1. pp. 56-64.
    @article{3016e4ec2afc4995a19d62b41e887cfe,
    title = "Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype",
    abstract = "Objective: 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. Methods: 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. Results: 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. Conclusion: 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.",
    keywords = "Atherosclerosis, Chronic kidney disease, Losartan, Macrophage phenotype, Pioglitazone, PPARγ",
    author = "Suguru Yamamoto and Jiayong Zhong and Yancey, {Patricia G.} and Yiqin Zuo and Linton, {MacRae F.} and Sergio Fazio and Haichun Yang and Ichiei Narita and Valentina Kon",
    year = "2015",
    month = "9",
    day = "1",
    doi = "10.1016/j.atherosclerosis.2015.06.055",
    language = "English (US)",
    volume = "242",
    pages = "56--64",
    journal = "Atherosclerosis",
    issn = "0021-9150",
    publisher = "Elsevier Ireland Ltd",
    number = "1",

    }

    TY - JOUR

    T1 - Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype

    AU - Yamamoto, Suguru

    AU - Zhong, Jiayong

    AU - Yancey, Patricia G.

    AU - Zuo, Yiqin

    AU - Linton, MacRae F.

    AU - Fazio, Sergio

    AU - Yang, Haichun

    AU - Narita, Ichiei

    AU - Kon, Valentina

    PY - 2015/9/1

    Y1 - 2015/9/1

    N2 - Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

    AB - Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

    KW - Atherosclerosis

    KW - Chronic kidney disease

    KW - Losartan

    KW - Macrophage phenotype

    KW - Pioglitazone

    KW - PPARγ

    UR - http://www.scopus.com/inward/record.url?scp=84938508700&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84938508700&partnerID=8YFLogxK

    U2 - 10.1016/j.atherosclerosis.2015.06.055

    DO - 10.1016/j.atherosclerosis.2015.06.055

    M3 - Article

    VL - 242

    SP - 56

    EP - 64

    JO - Atherosclerosis

    JF - Atherosclerosis

    SN - 0021-9150

    IS - 1

    ER -