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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jiayong
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Yancey
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Zuo
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Immunology and Microbiology, Vanderbilt University Medical Center, Nashville, TN, USA; Center for Preventive Cardiology at The Knight Cardiovascular Institute of Oregon Health and Science University, Portland, OR, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Haichun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.
authors.forename: Ichiei
authors.initials: I
authors.lastname: Narita
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: valentina.kon@vanderbilt.edu.
authors.forename: Valentina
authors.initials: V
authors.lastname: Kon
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001018:Aortic Diseases / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics; D007249:Inflammation; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy; D047495:PPAR gamma / Q000819:agonists; D010641:Phenotype; D000077205:Pioglitazone; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D012084:Renin-Angiotensin System / Q000187:drug effects; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001057:Apolipoproteins E; D016207:Cytokines; D047495:PPAR gamma; D045162:Thiazolidinediones; D019808:Losartan; D000077205:Pioglitazone
keywords: Atherosclerosis; Chronic kidney disease; Losartan; Macrophage phenotype; PPARγ; Pioglitazone