title: An AKI biomarker lipocalin 2 in the blood derives from the kidney in renal injury but from neutrophils in normal and infected conditions.
abstract: BACKGROUND
  Lipocalin 2 (LCN2 or neutrophil gelatinase-associated lipocalin) is a secretory protein discovered from neutrophils, which accumulates in the blood and urine during acute kidney injury (AKI) and in the blood by bacterial infection. Little is known about the tissue source and molecular forms of this protein under normal and pathophysiologic conditions.
  
  
  METHODS
  By sandwich ELISA, serum and urinary LCN2 levels were measured in 36 patients with hematologic malignancies who transiently became neutropenic by stem cell transplantation (SCT). To evaluate contribution of neutrophil-derived LCN2 in the physiologic blood LCN2 concentrations, we examined CCAAT/enhancer-binding protein ε (C/EBPε) knockout mice, which lack mature neutrophils.
  
  
  RESULTS
  In patients without AKI and bacterial infection, at 1 week after SCT, the median blood neutrophil counts became zero and serum LCN2 levels were decreased by 76 ± 6 % (p < 0.01), but urinary LCN2 levels were not altered. During neutropenic conditions, bacterial infection caused only a modest rise of serum LCN2 but AKI produced a marked rise of serum and urinary LCN2 levels. Serum LCN2 concentrations in C/EBPε knockout mice were reduced by 66 ± 11 % compared to wild-type mice (p < 0.05). Blood LCN2 existed predominantly in high molecular weight forms (>100 kDa), while urinary LCN2 was mainly in low molecular weight forms.
  
  
  CONCLUSIONS
  Our findings suggest that neutrophils are the major source of circulating LCN2 in normal and infected conditions, whereas blood and urinary LCN2 mainly derive from the kidney during AKI, and that the molecular forms and regulation of blood and urinary LCN2 are clearly distinct.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kanda
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawabata
authors.forename: Takashige
authors.initials: T
authors.lastname: Kuwabara
authors.forename: Keita P
authors.initials: KP
authors.lastname: Mori
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Imamaki
authors.forename: Masato
authors.initials: M
authors.lastname: Kasahara
authors.forename: Hideki
authors.initials: H
authors.lastname: Yokoi
authors.forename: Chisaki
authors.initials: C
authors.lastname: Mizumoto
authors.forename: Nils H
authors.initials: NH
authors.lastname: Thoennissen
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barasch
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukoyama
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood*; D000209:Acute-Phase Proteins / Q000652:urine; D000818:Animals; D001424:Bacterial Infections / Q000097:blood / Q000652:urine; D015415:Biomarkers / Q000097:blood / Q000652:urine; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000502:physiology; D019337:Hematologic Neoplasms / Q000150:complications / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood* / Q000652:urine; D051379:Mice; D018345:Mice, Knockout; D008970:Molecular Weight; D009504:Neutrophils / Q000378:metabolism*; D015513:Oncogene Proteins / Q000097:blood* / Q000652:urine
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; D022762:CCAAT-Enhancer-Binding Proteins; C489468:Cebpe protein, mouse; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; C071332:Lcn2 protein, mouse