Bile acids trigger cholemic nephropathy in common bile‐duct–ligated mice. Issue 6 (15th October 2013)

• Record Type: Journal Article
• Authors: Fickert, Peter; Krones, Elisabeth; Pollheimer, Marion J.; Thueringer, Andrea; Moustafa, Tarek; Silbert, Dagmar; Halilbasic, Emina; Yang, Min; Jaeschke, Hartmut; Stokman, Geurt; Wells, Rebecca G.; Eller, Kathrin; Rosenkranz, Alexander R.; Eggertsen, Gosta; Wagner, Carsten A.; Langner, Cord; Denk, Helmut; Trauner, Michael
• Is Part Of: Hepatology. Volume 58:Issue 6(2013:Dec.)
• Page Start: 2056
• Page End: 2069
• Publication Date: 2013-10-15
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.26599
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>in vivo</italic> 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 <italic>nor</italic>ursodeoxycholic acid inhibited renal tubular epithelial injury in CBDL mice. In addition, we provide evidence for renal tubular injury in cholestatic patients with cholemic nephropathy. <italic>Conclusion</italic>: We characterized a novel <italic>in vivo</italic> 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. (H<sc>epatology</sc> 2013; 58:2056–2069)</p> </abstract>