Macrophage angiotensin AT₂ receptor activation is protective against early phases of LPS-induced acute kidney injury

Lipopolysaccharide (LPS)-induced acute kidney injury (AKI) is characterized by inflammation and infiltration of immune cells, mainly neutrophils and macrophages, and results in sudden renal dysfunction. Previously, we have reported the anti-inflammatory and renoprotective role of the angiotensin II type 2 receptor (AT₂R), expressed on kidney tubular cells and immune cells, in LPS-induced AKI. Moreover, in vitro studies revealed macrophage AT₂R activation shifts the cells to the anti-inflammatory M2 subtype. However, the protective role of the macrophage AT₂R in a model of AKI is unknown. The present study addressed this question by adoptive transfer of bone marrow-derived macrophages (BMDMs) in systemic macrophage-depleted mice. We acquired significant systemic macrophage depletion by two doses of liposomal clodronate (CLD), and the mice were repopulated with BMDMs (CD11b⁺F4/80⁺, double positive) primed with AT₂R agonist C21 (CLD + MacC21 + LPS) or vehicle (CLD + Mac + LPS) in vitro for 60 min, followed by LPS (5 mg/kg body wt ip) challenge. We observed a gradual increase in the CD11b⁺ cells at 2 and 24 h after the LPS challenge. However, kidney CD11b⁺ cells in the CLD + Mac + LPS group were elevated compared with the CLD + MacC21 + LPS group at 2 h after the LPS challenge. The level of inflammatory cytokine (tumor necrosis factor-α) was elevated at 2 h, which was reduced significantly in CLD + MacC21 + LPS-treated animals. Also, CLD + MacC21 + LPS-treated animals had elevated plasma and renal IL-10, indicating an anti-inflammatory role of C21-treated BMDMs. Renal functional injury in CLD + MacC21 + LPS-treated animals was partially improved. Collectively, the data demonstrate that BMDM AT₂R stimulation results in anti-inflammation and partial renoprotection against early stages of LPS-induced AKI.NEW & NOTEWORTHY Endotoxin such as lipopolysaccharide (LPS) induces acute kidney injury (AKI), which is a risk factor for and often leads to chronic kidney diseases. The present study revealed that bone marrow-derived macrophage activation of the angiotensin II type 2 receptor (AT₂R) contributes to the anti-inflammation and partial renoprotection against early stages of LPS-induced AKI. Since AT₂R is an emerging anti-inflammatory and organ-protective target, this study advances our understanding of AT₂R's anti-inflammatory mechanisms associated with renoprotection.