Arginase-1 Is Required for Macrophage-Mediated Renal Tubule Regeneration.

Abstract

After kidney injury, macrophages transition from initial proinflammatory activation to a proreparative phenotype characterized by expression of arginase-1 (<i>Arg1</i>), mannose receptor 1 (<i>Mrc1</i>), and macrophage scavenger receptor 1 (<i>Msr1</i>). The mechanism by which these alternatively activated macrophages promote repair is unknown. We characterized the macrophage and renal responses after ischemia-reperfusion injury with contralateral nephrectomy in <i>LysM-Cre;Arg1^fl/fl</i> mice and littermate controls and used <i>in vitro</i> coculture of macrophages and tubular cells to determine how macrophage-expressed arginase-1 promotes kidney repair. After ischemia-reperfusion injury with contralateral nephrectomy, <i>Arg1</i>-expressing macrophages were almost exclusively located in the outer stripe of the medulla adjacent to injured S3 tubule segments containing luminal debris or casts. Macrophage <i>Arg1</i> expression was reduced by more than 90% in injured <i>LysM-Cre;Arg1^fl/fl</i> mice, resulting in decreased mouse survival, decreased renal tubular cell proliferation and decreased renal repair compared with littermate controls. <i>In vitro</i> studies demonstrate that tubular cells exposed apically to dead cell debris secrete high levels of GM-CSF and induce reparative macrophage activation, with those macrophages in turn secreting <i>Arg1</i>-dependent factor(s) that directly stimulate tubular cell proliferation. GM-CSF-induced, proreparative macrophages express arginase-1, which is required for the S3 tubular cell proliferative response that promotes renal repair after ischemia-reperfusion injury.