title: Lipocalin-2-induced renal regeneration depends on cytokines.
abstract: 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 min of renal ischemia with a reperfusion period of 24 h (early reperfusion, expected time for maximum inflammation) and 96 h (late reperfusion, expected time for maximum regeneration). Different experimental groups underwent I/R, I/R with iv anti-mouse Lcn2 monoclonal antibody injected during the early/inflammatory or late/recovery phase, and I/R with proinflammatory cytokine cocktail administration (recombinant mouse IL-1beta, TNF-alpha, and IFN-gamma). Compared with control nonischemic 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. Blockade 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. Proinflammatory 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.
authors.affiliation: Department of Experimental Pathology, Instituto de Investigactiones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas-Institut de Investigacions Biomédiques August Pi i Sunyer, Spain.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Vinuesa
authors.forename: Anna
authors.initials: A
authors.lastname: Sola
authors.forename: Michaela
authors.initials: M
authors.lastname: Jung
authors.forename: Vicente
authors.initials: V
authors.lastname: Alfaro
authors.forename: Georgina
authors.initials: G
authors.lastname: Hotter
mesh_terms: D000209:Acute-Phase Proteins / Q000276:immunology / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics; D053583:Interleukin-1beta / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000276:immunology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D015513:Oncogene Proteins / Q000276:immunology / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D015427:Reperfusion Injury / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050777:Stathmin / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000209:Acute-Phase Proteins; D000911:Antibodies, Monoclonal; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D053583:Interleukin-1beta; D019394:Ki-67 Antigen; D000071068:Lipocalin-2; D054834:Lipocalins; D008070:Lipopolysaccharides; D015513:Oncogene Proteins; D018809:Proliferating Cell Nuclear Antigen; D050777:Stathmin; C493994:Stmn1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C071332:Lcn2 protein, mouse; D016753:Interleukin-10; D007371:Interferon-gamma