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Abstract: FR-OR024

IL-6-Mediated Hepatocyte Production Is the Primary Source of Plasma and Urine Neutrophil Gelatinase-Associated Lipocalin (NGAL) During AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Skrypnyk, Nataliya, University of Colorado, Denver, Colorado, United States
  • Faubel, Sarah, University of Colorado Denver, Denver, Colorado, United States
Background

NGAL (Lcn2) is the most widely studied biomarker of acute kidney injury (AKI); however the ability of NGAL to predict AKI has been mixed, possibly because it is produced by cell types outside of the kidney or in response to other stimuli such as systemic inflammation. In the present study, we investigated renal and extra-renal NGAL production in response to the proinflammatory cytokine IL-6.

Methods

Mice: C57Bl/6J (WT)/ B6.IL6<tm1Kopf>/J (IL-6-/-), hepatocyte specific Lcn2 deficient (Lcn2hep-/-)/cre- littermates. Procedures: sham, kidney ischemia reperfusion (IR) (27 minutes bilateral renal pedicle clamping); bilateral nephrectomy (Bnx). Injections: anti-mouse Ly6G clone 1A8/rat IgG2a isotype control clone 2A3 500μg, IP; recombinant murine (rm)IL-6 (200 ng, IV). Measurements: BUN, plasma creatinine, Kim1 mRNA, NGAL mRNA (liver kidney, spleen and lung); NGAL protein concentrations (liver, kidney, spleen, lung, plasma and urine).

Results

Plasma NGAL was increased in WT 4 and 24 hours after sham, IR, and BNx and was decreased in IL-6-/- mice in all three conditions; similarly, urine NGAL was increased after sham and IR in WT and decreased in IL-6-/- mice. Kidney function was similar between WT and IL-6-/- mice as judged by serum creatinine, BUN, and kidney histology. NGAL mRNA was most upregulated in the liver (versus the kidney, lung, and spleen) 4 and 24 hours after sham, IR, and BNx, and reduced in IL-6-/-mice. IV injection of recombinant IL-6 to normal mice resulted in a significant increase in hepatic, but not renal, NGAL mRNA and an increase in plasma and urine NGAL. In vitro, addition of recombinant IL-6 to hepatocytes resulted in a significant increase in NGAL levels in the supernatant. To further examine the specific contribution of hepatocytes to plasma and urine NGAL levels, mice with hepatocyte specific NGAL deletion (Lcn2hep-/-) were studied; plasma and urine NGAL were 90% and 80% reduced, respectively, after IR. Neutrophil depletion after IR did not affect plasma and urine NGAL levels after sham and IR.

Conclusion

IL-6 mediates hepatic production of NGAL during AKI. The results of these experiments shed new insights into the mechanism behind the increases in plasma and urine NGAL after AKI.

Funding

  • Veterans Affairs Support