Bile acids trigger cholemic nephropathy in common bile-duct–ligated mice

Authors

  • Peter Fickert,

    Corresponding author
    1. Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
    2. Department of Pathology, Medical University of Graz, Graz, Austria
    • Address reprint requests to: Peter Fickert, M.D., Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. E-mail: peter.fickert@medunigraz.at; fax: +43 316-385-17108; Michael Trauner, M.D., Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Wien, Austria. E-mail: michael.trauner@meduniwien.ac.at; fax: +43 1-40400-4735.

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    • These authors contributed equally to this work.

  • Elisabeth Krones,

    1. Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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    • These authors contributed equally to this work.

  • Marion J. Pollheimer,

    1. Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
    2. Department of Pathology, Medical University of Graz, Graz, Austria
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  • Andrea Thueringer,

    1. Department of Pathology, Medical University of Graz, Graz, Austria
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  • Tarek Moustafa,

    1. Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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  • Dagmar Silbert,

    1. Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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  • Emina Halilbasic,

    1. Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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  • Min Yang,

    1. Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS
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  • Hartmut Jaeschke,

    1. Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS
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  • Geurt Stokman,

    1. Division of Toxicology, LACDR, Leiden University, Leiden, The Netherlands
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  • Rebecca G. Wells,

    1. Department of Medicine, University of Pennsylvania, Philadelphia, PA
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  • Kathrin Eller,

    1. Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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  • Alexander R. Rosenkranz,

    1. Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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  • Gosta Eggertsen,

    1. Karolinska Institutet, Department of Medicine at Karolinska University Hospital Huddinge, Stockholm, Sweden
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  • Carsten A. Wagner,

    1. Institute of Physiology and Center for Human Integrative Physiology, University of Zurich, Zurich, Switzerland
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  • Cord Langner,

    1. Department of Pathology, Medical University of Graz, Graz, Austria
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  • Helmut Denk,

    1. Department of Pathology, Medical University of Graz, Graz, Austria
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  • Michael Trauner

    1. Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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  • Potential conflict of interest: Nothing to report.

Abstract

Tubular epithelial injury represents an underestimated but important cause of renal dysfunction in patients with cholestasis and advanced liver disease, but the underlying mechanisms are unclear. To address the hypothesis that accumulation and excessive alternative urinary elimination of potentially toxic bile acids (BAs) may contribute to kidney injury in cholestasis, we established a mouse model for detailed in vivo time course as well as treatment studies. Three-day common bile duct ligation (CBDL) induced renal tubular epithelial injury predominantly at the level of aquaporin 2–positive collecting ducts with tubular epithelial and basement membrane defects. This was followed by progressive interstitial nephritis and tubulointerstitial renal fibrosis in 3-, 6-, and 8-week CBDL mice. Farnesoid X receptor knockout mice (with a hydrophilic BA pool) were completely protected from CBDL-induced renal fibrosis. Prefeeding of hydrophilic norursodeoxycholic acid inhibited renal tubular epithelial injury in CBDL mice. In addition, we provide evidence for renal tubular injury in cholestatic patients with cholemic nephropathy. Conclusion: We characterized a novel in vivo model for cholemic nephropathy, which offers new perspectives to study the complex pathophysiology of this condition. Our findings suggest that urinary-excreted toxic BAs represent a pivotal trigger for renal tubular epithelial injury leading to cholemic nephropathy in CBDL mice. (Hepatology 2013; 58:2056–2069)

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