Macrophage/monocyte depletion by clodronate, but not diphtheria toxin, improves renal ischemia/reperfusion injury in mice

Kidney Int. 2012 Oct;82(8):928-33. doi: 10.1038/ki.2012.207. Epub 2012 Jun 6.

Abstract

The role of resident renal mononuclear phagocytes in acute kidney injury is controversial with experimental data suggesting both deleterious and protective functions. To help resolve this, we used mice transgenic for the human diphtheria toxin receptor under the control of the CD11b promoter and treated them with diphtheria toxin, or liposomal clodronate, or both to deplete monocyte/mononuclear phagocytes prior to renal ischemia/reperfusion injury. Although either system effectively depleted circulating monocytes and resident mononuclear phagocytes, depletion was most marked in diphtheria toxin-treated mice. Despite this, diphtheria toxin treatment did not protect from renal ischemia. In contrast, mice treated with clodronate exhibited reduced renal failure and acute tubular necrosis, suggesting key differences between these depletion strategies. Clodronate did not deplete CD206-positive renal macrophages and, unlike diphtheria toxin, left resident CD11c-positive cells unscathed while inducing dramatic apoptosis in hepatic and splenic mononuclear phagocyte populations. Abolition of the protected phenotype by administration of diphtheria toxin to clodronate-treated mice suggested that the protective effect of clodronate resulted from the presence of a cytoprotective intrarenal population of mononuclear phagocytes sensitive to diphtheria toxin-mediated ablation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / drug therapy*
  • Acute Kidney Injury / pathology
  • Animals
  • CD11b Antigen / genetics
  • CD11c Antigen / metabolism
  • Clodronic Acid / pharmacology*
  • Diphtheria Toxin / pharmacology
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Ischemia / drug therapy
  • Ischemia / pathology
  • Kidney / blood supply
  • Kidney / drug effects
  • Kidney / pathology
  • Lectins, C-Type / metabolism
  • Macrophages / drug effects*
  • Macrophages / pathology
  • Macrophages / physiology
  • Male
  • Mannose-Binding Lectins / metabolism
  • Mice
  • Mice, Transgenic
  • Monocytes / drug effects*
  • Monocytes / pathology
  • Monocytes / physiology
  • Promoter Regions, Genetic
  • Receptors, Cell Surface / metabolism
  • Recombinant Proteins / genetics
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / pathology

Substances

  • CD11b Antigen
  • CD11c Antigen
  • Diphtheria Toxin
  • HBEGF protein, human
  • Hbegf protein, mouse
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Lectins, C-Type
  • Mannose-Binding Lectins
  • Receptors, Cell Surface
  • Recombinant Proteins
  • mannose receptor
  • Clodronic Acid