Macrophage Polarization by Angiotensin II-Type 1 Receptor Aggravates Renal Injury-Acceleration of Atherosclerosis

Abstract

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). 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 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 ^+/+ . 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.