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

Significance Statement Proinflammatory macrophages that infiltrate the kidney after ischemia-reperfusion injury later transition to a proreparative state characterized by expression of multiple proteins including arginase-1 ( Arg1 ). By comparing the kidney repair response after ischemia-reperfusion injury in mice that lack macrophage Arg1 expression with littermate controls, we show that macrophage Arg1 plays a critical role in renal recovery in part by promoting renal epithelial cell proliferative repair. Thus, therapeutic interventions that enhance Arg1 expression may improve renal recovery after kidney injury. Background After kidney injury, macrophages transition from initial proinflammatory activation to a proreparative phenotype characterized by expression of arginase-1 ( Arg1 ), mannose receptor 1 ( Mrc1 ), and macrophage scavenger receptor 1 ( Msr1 ). The mechanism by which these alternatively activated macrophages promote repair is unknown. Methods We characterized the macrophage and renal responses after ischemia-reperfusion injury with contralateral nephrectomy in LysM-Cre;Arg1fl/fl mice and littermate controls and used in vitro coculture of macrophages and tubular cells to determine how macrophage-expressed arginase-1 promotes kidney repair. Results After ischemia-reperfusion injury with contralateral nephrectomy, Arg1 -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 Arg1 expression was reduced by more than 90% in injured LysM-Cre;Arg1fl/fl mice, resulting in decreased mouse survival, decreased renal tubular cell proliferation and decreased renal repair compared with littermate controls. In vitro 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 Arg1 -dependent factor(s) that directly stimulate tubular cell proliferation. Conclusions 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.