IL-6-mediated hepatocyte production is the primary source of plasma and urine neutrophil gelatinase-associated lipocalin during acute kidney injury
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 injur...
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| Vydané v: | Kidney international Ročník 97; číslo 5; s. 966 |
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| Hlavní autori: | , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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United States
01.05.2020
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| Abstract | 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. |
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| AbstractList | 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. 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.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. |
| Author | Gist, Katja M Bodoni, Evelyn Altmann, Chris Edelstein, Charles L Montford, John R Yang, Haichun Kirkbride-Romeo, Lara A Moldovan, Radu Skrypnyk, Nataliya I Blaine, Judith T Griffin, Benjamin R Faubel, Sarah Okamura, Kayo Soranno, Danielle E You, Zhiying |
| Author_xml | – sequence: 1 givenname: Nataliya I surname: Skrypnyk fullname: Skrypnyk, Nataliya I organization: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA – sequence: 2 givenname: Katja M surname: Gist fullname: Gist, Katja M organization: Department of Cardiology, The Heart Institute, Children's Hospital Colorado, Aurora, Colorado, USA – sequence: 3 givenname: Kayo surname: Okamura fullname: Okamura, Kayo organization: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA – sequence: 4 givenname: John R surname: Montford fullname: Montford, John R organization: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA; Renal Section, Rocky Mountain Regional VA Medical Center, Aurora, Colorado, USA – sequence: 5 givenname: Zhiying surname: You fullname: You, Zhiying organization: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA – sequence: 6 givenname: Haichun surname: Yang fullname: Yang, Haichun organization: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA – sequence: 7 givenname: Radu surname: Moldovan fullname: Moldovan, Radu organization: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA; Advanced Light Microscopy Core Facility, Aurora, Colorado, USA – sequence: 8 givenname: Evelyn surname: Bodoni fullname: Bodoni, Evelyn organization: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA; Advanced Light Microscopy Core Facility, Aurora, Colorado, USA – sequence: 9 givenname: Judith T surname: Blaine fullname: Blaine, Judith T organization: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA – sequence: 10 givenname: Charles L surname: Edelstein fullname: Edelstein, Charles L organization: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA – sequence: 11 givenname: Danielle E surname: Soranno fullname: Soranno, Danielle E organization: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA; Department of Pediatrics and Bioengineering, University of Colorado, Aurora, Colorado, USA – sequence: 12 givenname: Lara A surname: Kirkbride-Romeo fullname: Kirkbride-Romeo, Lara A organization: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA – sequence: 13 givenname: Benjamin R surname: Griffin fullname: Griffin, Benjamin R organization: Department of Medicine, Division of Nephrology, University of Iowa, Iowa City, Iowa, USA – sequence: 14 givenname: Chris surname: Altmann fullname: Altmann, Chris organization: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA – sequence: 15 givenname: Sarah surname: Faubel fullname: Faubel, Sarah email: sarah.faubel@ucdenver.edu organization: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA; Renal Section, Rocky Mountain Regional VA Medical Center, Aurora, Colorado, USA. Electronic address: sarah.faubel@ucdenver.edu |
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| Keywords | ischemia reperfusion acute kidney injury cytokines nephrotoxicity biomarkers IL-6 |
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