title: Macrophage polarization by angiotensin II-type 1 receptor aggravates renal injury-acceleration of atherosclerosis.
abstract: OBJECTIVE
  Angiotensin II is a major determinant of atherosclerosis. Although macrophages are the most abundant cells in atherosclerotic plaques and express angiotensin II type 1 receptor (AT1), the pathophysiologic role of macrophage AT1 in atherogenesis remains uncertain. We examined the contribution of macrophage AT1 to accelerated atherosclerosis in an angiotensin II-responsive setting induced by uninephrectomy (UNx).
  
  
  RESULTS
  AT1(-/-) or AT1(+/+) marrow from apolipoprotein E deficient (apoE(-/-)) mice was transplanted into recipient apoE(-/-) mice with subsequent UNx or sham operation: apoE(-/-)/AT1(+/+)→apoE(-/-)+sham; apoE(-/-)/AT1(+/+) →apoE(-/-)+UNx; apoE(-/-)/AT1(-/-)→apoE(-/-)+sham; apoE(-/-)/AT1(-/-)→apoE(-/-)+UNx. No differences in body weight, blood pressure, lipid profile, and serum creatinine were observed between the 2 UNx groups. ApoE(-/-)/AT1(+/+) →apoE(-/-)+UNx had significantly more atherosclerosis (16907±21473 versus 116071±8180 μm(2), P<0.05). By contrast, loss of macrophage AT1 which reduced local AT1 expression, prevented any effect of UNx on atherosclerosis (77174±9947 versus 75714±11333 μm(2), P=NS). Although UNx did not affect total macrophage content in the atheroma, lesions in apoE(-/-)/AT1(-/-)→apoE(-/-)+UNx had fewer classically activated macrophage phenotype (M1) and more alternatively activated phenotype (M2). Further, UNx did not affect plaque necrosis or apoptosis in apoE(-/-)/AT1(-/-)→apoE(-/-) whereas it significantly increased both (by 2- and 6-fold, respectively) in apoE(-/-)/AT1(+/+) →apoE(-/-) mice. Instead, apoE(-/-)/AT1(-/-)→apoE(-/-) had 5-fold-increase in macrophage-associated apoptotic bodies, indicating enhanced efferocytosis. In vitro studies confirmed blunted susceptibility to apoptosis, especially in M2 macrophages, and a more efficient phagocytic function of AT1(-/-) macrophages versus AT1(+/+).
  
  
  CONCLUSIONS
  AT1 receptor of bone marrow-derived macrophages worsens the extent and complexity of renal injury-induced atherosclerosis by shifting the macrophage phenotype to more M1 and less M2 through mechanisms that include increased apoptosis and impaired efferocytosis.
authors: Department of Pediatrics, Vanderbilt University Medical Center, 1161 21st Avenue South, C-4204 Medical Center North, Nashville, TN 37232-2584, USA.
authors: Suguru
authors: S
authors: Yamamoto
authors: Patricia G
authors: PG
authors: Yancey
authors: Yiqin
authors: Y
authors: Zuo
authors: Li-Jun
authors: LJ
authors: Ma
authors: Ryohei
authors: R
authors: Kaseda
authors: Agnes B
authors: AB
authors: Fogo
authors: Iekuni
authors: I
authors: Ichikawa
authors: MacRae F
authors: MF
authors: Linton
authors: Sergio
authors: S
authors: Fazio
authors: Valentina
authors: V
authors: Kon
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications* / Q000209:etiology; D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D016764:Cell Polarity / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy / Q000009:adverse effects; D010641:Phenotype; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II