IL-6-mediated hepatocyte production is the primary source of plasma and urine neutrophil gelatinase-associated lipocalin during acute kidney injury.
IL-6
acute kidney injury
biomarkers
cytokines
ischemia reperfusion
nephrotoxicity
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
08
01
2019
revised:
09
10
2019
accepted:
01
11
2019
pubmed:
23
2
2020
medline:
22
6
2021
entrez:
22
2
2020
Statut:
ppublish
Résumé
Neutrophil gelatinase associated lipocalin (NGAL, Lcn2) is the most widely studied biomarker of acute kidney injury (AKI). Previous studies have demonstrated that NGAL is produced by the kidney and released into the urine and plasma. Consequently, NGAL is currently considered a tubule specific injury marker of AKI. However, the utility of NGAL to predict AKI has been variable suggesting that other mechanisms of production are present. IL-6 is a proinflammatory cytokine increased in plasma by two hours of AKI and mediates distant organ effects. Herein, we investigated the role of IL-6 in renal and extra-renal NGAL production. Wild type mice with ischemic AKI had increased plasma IL-6, increased hepatic NGAL mRNA, increased plasma NGAL, and increased urine NGAL; all reduced in IL-6 knockout mice. Intravenous IL-6 in normal mice increased hepatic NGAL mRNA, plasma NGAL and urine NGAL. In mice with hepatocyte specific NGAL deletion (Lcn2hep-/-) and ischemic AKI, hepatic NGAL mRNA was absent, and plasma and urine NGAL were reduced. Since urine NGAL levels appear to be dependent on plasma levels, the renal handling of circulating NGAL was examined using recombinant human NGAL. After intravenous recombinant human NGAL administration to mice, human NGAL in mouse urine was detected by ELISA during proximal tubular dysfunction, but not in pre-renal azotemia. Thus, during AKI, IL-6 mediates hepatic NGAL production, hepatocytes are the primary source of plasma and urine NGAL, and plasma NGAL appears in the urine during proximal tubule dysfunction. Hence, our data change the paradigm by which NGAL should be interpreted as a biomarker of AKI.
Identifiants
pubmed: 32081304
pii: S0085-2538(19)31154-8
doi: 10.1016/j.kint.2019.11.013
pmc: PMC8409721
mid: NIHMS1563527
pii:
doi:
Substances chimiques
Acute-Phase Proteins
0
Biomarkers
0
Interleukin-6
0
Lipocalin-2
0
Lipocalins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
966-979Subventions
Organisme : BLRD VA
ID : I01 BX001498
Pays : United States
Organisme : NIDDK NIH HHS
ID : K08 DK109226
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130084
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007135
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS048154
Pays : United States
Organisme : BLRD VA
ID : IK2 BX003839
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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