title: Macrophage-derived Lipocalin-2 contributes to ischemic resistance mechanisms by protecting from renal injury.
abstract: 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.
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Jung
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.affiliation: Department of Ischemia and Inflammation, IIBB-CSIC-IDIBAPS, Barcelona, Spain.|CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain.
authors.forename: Georgina
authors.initials: G
authors.lastname: Hotter
authors.affiliation: CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain.|Department of Experimental Nephrology, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Sola
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D001854:Bone Marrow Cells / Q000166:cytology; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D000071068:Lipocalin-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D019394:Ki-67 Antigen; D000071068:Lipocalin-2; D008070:Lipopolysaccharides; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D003404:Creatinine