This study investigated whether the renal regeneration occurring in the recovery phase of kidney ischemia/reperfusion (I/R) is mediated by endogenously generated lipocalin-2 (Lcn2). A second objective was to examine whether Lcn2-mediated cell effects could be regulated by the inflammatory cytokines in the environment through their action on Lcn2 receptors (Lcn2R and megalin). Male Swiss mice were subjected to 30 minutes of renal ischemia with a reperfusion period of 24 hours (early reperfusion, expected time for maximum inflammation) and 96 hours (late reperfusion, expected time for maximum regeneration). Different experimental groups underwent I/R, I/R with i.v. anti-mouse Lcn2 monoclonal antibody injected during the early/inflammatory or late/recovery phase, and I/R with pro-inflammatory cytokine cocktail administration (recombinant mouse IL-1, TNF- and IFN-_.). Compared to control non-ischemic mice, the expression of three proliferation markers (stathmin, PCNA and Ki-67, analyzed by quantitative RT-PCR) increased significantly in the I/R treated animals. Blockage of Lcn2 by addition of anti-Lcn2 antibody significantly decreased the expression of these three proliferation markers when administered in the late/reparative phase, but had the opposite effect when administered in the early/inflammatory phase. Pro-inflammatory cytokine cocktail administration reduced the proliferative effects of Lcn2, and repressed Lcn2R and megalin expression. In conclusion, endogenously generated Lcn2 induces renal cell regeneration depending on the inflammatory cytokines in kidney I/R.