Heme Oxygenase-1 Regulates Myeloid Cell Trafficking in AKI.

Academic Article

Abstract

  • 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(hi)F4/80(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(lo)F4/80(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.
  • Keywords

  • ARF, heme oxygenase, macrophages, Acute Kidney Injury, Animals, Cell Movement, Dendritic Cells, Fibrosis, Heme Oxygenase-1, Immunity, Innate, Interleukin-6, Ischemia, Kidney, Lymph Nodes, Macrophages, Male, Mice, Mice, Knockout, Mice, Transgenic, Myeloid Cells, Neutrophils, Reperfusion Injury, Spleen, Tumor Necrosis Factor-alpha
  • Digital Object Identifier (doi)

    Authorlist

  • Hull TD; Kamal AI; Boddu R; Bolisetty S; Guo L; Tisher CC; Rangarajan S; Chen B; Curtis LM; George JF
  • Start Page

  • 2139
  • End Page

  • 2151
  • Volume

  • 26
  • Issue

  • 9