Heme Oxygenase-1 Regulates Myeloid Cell Trafficking in AKI

Renal ischemia-reperfusion injury is mediated by a complex cascade of events, including the immune response, that occur secondary to injury to renal epithelial cells. We tested the hypothesis that heme oxygenase-1 (HO-1) expression, which is protective in ischemia-reperfusion injury, regulates trafficking of myeloid-derived immune cells in the kidney. Age-matched male wild-type (HO-1^+/+), HO-1–knockout (HO-1^−/−), and humanized HO-1–overexpressing (HBAC) mice underwent bilateral renal ischemia for 10 minutes. Ischemia-reperfusion injury resulted in significantly worse renal structure and function and increased mortality in HO-1^−/− mice. In addition, there were more macrophages (CD45⁺ CD11b^hiF4/80^lo) and neutrophils (CD45⁺ CD11b^hi MHCII⁻ Gr-1^hi) in HO-1^−/− kidneys than in sham and HO-1^+/+ control kidneys subjected to ischemia-reperfusion. However, ischemic injury resulted in a significant decrease in the intrarenal resident dendritic cell (DC; CD45⁺MHCII⁺CD11b^loF4/80^hi) population in HO-1^−/− kidneys compared with controls. Syngeneic transplant experiments utilizing green fluorescent protein–positive HO-1^+/+ or HO-1^−/− donor kidneys and green fluorescent protein–negative HO-1^+/+ recipients confirmed increased migration of the resident DC population from HO-1^−/− donor kidneys, compared to HO-1^+/+ donor kidneys, to the peripheral lymphoid organs. This effect on renal DC migration was corroborated in myeloid-specific HO-1^−/− mice subjected to bilateral ischemia. These mice also displayed impaired renal recovery and increased fibrosis at day 7 after injury. These results highlight an important role for HO-1 in orchestrating the trafficking of myeloid cells in AKI, which may represent a key pathway for therapeutic intervention.