title: NorUrsodeoxycholic acid ameliorates cholemic nephropathy in bile duct ligated mice.
abstract: Severe cholestasis may cause cholemic nephropathy that can be modeled in common bile duct ligated (CBDL) mice. We aimed to explore the therapeutic efficacy and mechanisms of norursodeoxycholic acid (norUDCA) in cholemic nephropathy.
  
  
  
  In 8-week CBDL mice fed with norUDCA (prior or post CBDL) or chow we evaluated serum urea levels, urine cytology and urinary neutrophil gelatinase associated lipocalin (uNGAL), kidney and liver tissue quantification of fibrosis by hydroxyproline content and gene chip expression looking at key genes of inflammation and fibrosis. Moreover, we comprehensively analysed bile acid profiles in liver, kidney, serum and urine samples.
  
  
  
  NorUDCA-fed CBDL mice had significantly lower serum urea and uNGAL levels and less severe cholemic nephropathy as demonstrated by normal urine cytology, significantly reduced tubulointerstitial nephritis, and renal fibrosis as compared to controls. NorUDCA underwent extensive metabolism to produce even more hydrophilic compounds that were significantly enriched in kidneys.
  
  
  
  NorUDCA ameliorates cholemic nephropathy due to the formation of highly hydrophilic metabolites enriched in kidney. Consequently, norUDCA may represent a medical treatment for cholemic nephropathy.
  
  
  
  The term cholemic nephropathy describes renal dysfunction together with characteristic morphological alterations of the kidney in obstructive cholestasis that can be mimicked by ligation of the common bile duct in mice. Feeding the hydrophilic bile acid norUDCA to bile duct ligated mice leads to a significant amelioration of the renal phenotype due to the formation of highly hydrophilic metabolites enriched in the kidney and may therefore represent a medical treatment for cholemic nephropathy.
authors.affiliation: Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Krones
authors.affiliation: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Austria.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Eller
authors.affiliation: Department of Pathology, Medical University of Graz, Austria.
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Pollheimer
authors.affiliation: Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Racedo
authors.affiliation: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Austria.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Kirsch
authors.affiliation: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Austria.
authors.forename: Bianca
authors.initials: B
authors.lastname: Frauscher
authors.affiliation: Sahlgrenska Academy, Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Wahlström
authors.affiliation: Sahlgrenska Academy, Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ståhlman
authors.affiliation: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Grahammer
authors.affiliation: Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, Germany; BIOSS Center for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany; FRIAS - Freiburg Institute for Advanced Studies and ZBSA - Center for Systems Biology, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.affiliation: Core Facility Molecular Biology, Center for Medical Research, Medical University Graz, Graz, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Austria.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Rosenkranz
authors.affiliation: Sahlgrenska Academy, Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.affiliation: Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria. Electronic address: peter.fickert@medunigraz.at.
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000652:urine; D002779:Cholestasis / Q000150:complications*; D004195:Disease Models, Animal; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy*; D008026:Ligation; D000071068:Lipocalin-2 / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000188:drug therapy; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D001647:Bile Acids and Salts; D000071068:Lipocalin-2; D014580:Ursodeoxycholic Acid; C081331:24-norursodeoxycholic acid
keywords: Acute kidney injury; Bile acid therapy; Bile acids; Bile cast nephropathy; Kidney fibrosis; Liver cirrhosis; Renal failure