Macrophage-derived Lipocalin-2 contributes to ischemic resistance mechanisms by protecting from renal injury

Sci Rep. 2016 Feb 25:6:21950. doi: 10.1038/srep21950.


Renal ischemia-reperfusion injury triggers an inflammatory response associated to infiltrating macrophages which determines the further outcome of disease. Brown Norway rats are known to show endogenous resistance to ischemia-induced renal damage. By contrast, Sprague Dawley rats exhibit a higher susceptibility to ischemic injury. In order to ascertain cytoprotective mechanisms, we focused on the implication of lipocalin-2 protein in main resistance mechanisms in renal ischemia/reperfusion injury by using adoptive macrophage administration, genetically modified ex vivo either to overexpress or to knockdown lipocalin-2. In vitro experiments with bone marrow-derived macrophages both from Brown Norway rats and from Sprague Dawley rats under hypoxic conditions showed endogenous differences regarding cytokine and lipocalin-2 expression profile in the two strains. Most interestingly, we observed that macrophages of the resistant strain express significantly more lipocalin-2. In vivo studies showed that tubular epithelial cell apoptosis and renal injury significantly increased and reparative markers decreased in Brown Norway rats after injection of lipocalin-2-knockdown macrophages, while the administration of lipocalin-2-overexpressing cells significantly decreased Sprague Dawley susceptibility. These data point to a crucial role of macrophage-derived lipocalin-2 in endogenous cytoprotective mechanisms. We conclude that expression of lipocalin-2 in tissue-infiltrating macrophages is pivotal for kidney-intrinsic cytoprotective pathways during ischemia reperfusion injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Urea Nitrogen
  • Bone Marrow Cells / cytology
  • CD11b Antigen / metabolism
  • Cells, Cultured
  • Creatinine / blood
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Flow Cytometry
  • Ki-67 Antigen / genetics
  • Ki-67 Antigen / metabolism
  • Kidney / metabolism
  • Kidney / pathology
  • Lipocalin-2 / antagonists & inhibitors
  • Lipocalin-2 / genetics
  • Lipocalin-2 / metabolism*
  • Lipopolysaccharides / toxicity
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Male
  • Microscopy, Fluorescence
  • Proliferating Cell Nuclear Antigen / genetics
  • Proliferating Cell Nuclear Antigen / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Inbred BN
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology*
  • Reperfusion Injury / prevention & control


  • CD11b Antigen
  • Cytokines
  • Ki-67 Antigen
  • Lipocalin-2
  • Lipopolysaccharides
  • Proliferating Cell Nuclear Antigen
  • RNA, Small Interfering
  • Creatinine