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An AKI biomarker lipocalin 2 in the blood derives from the kidney in renal injury but from neutrophils in normal and infected conditions

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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.

Conclusion

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.

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Acknowledgments

The authors are grateful to Drs. K. Xanthopolous (Aurora Biosciences, San Diego, CA) and J. Lekstrom-Himes (the National Institutes of Health, Bethesda, MD) for providing C/EBPε knockout mice. C/EBP α cDNA was a kind gift from Dr. D.G. Tenen (Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA). We also want to thank Ms. M. Nakaya (Abbott Japan, Matsudo, Japan) for discussion. This work was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan (K.M., H.K. and M.M.), the Japan Kidney Foundation (K.M.), the Project Research from the High-Technology Center of Kanazawa Medical University (H.K.), the Smoking Research Foundation (M.M.), and the National Institutes of Health and A*STAR of Singapore (H.P.K.).

Conflict of interest

K.M. and J.B. are a part of patent co-inventors for LCN2 as a diagnostic marker of renal failure. The other authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Junya Kanda, Hiroshi Kawabata, Chisaki Mizumoto & Akifumi Takaori-Kondo

  2. Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyoku, Kyoto, 606-8507, Japan

    Kiyoshi Mori, Takashige Kuwabara, Keita P. Mori, Hirotaka Imamaki, Masato Kasahara, Hideki Yokoi, Masashi Mukoyama & Kazuwa Nakao

  3. Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA

    Nils H. Thoennissen & H. Phillip Koeffler

  4. Department of Medicine, Physicians and Surgeons of Columbia University, New York, NY, USA

    Jonathan Barasch

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  1. Junya Kanda
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  2. Kiyoshi Mori
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Correspondence to Kiyoshi Mori.

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Kanda, J., Mori, K., Kawabata, H. et al. An AKI biomarker lipocalin 2 in the blood derives from the kidney in renal injury but from neutrophils in normal and infected conditions. Clin Exp Nephrol 19, 99–106 (2015). https://doi.org/10.1007/s10157-014-0952-7

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  • DOI: https://doi.org/10.1007/s10157-014-0952-7

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