Elisabeth Krones1, Kathrin Eller2, Marion J Pollheimer3, Silvia Racedo1, Alexander H Kirsch2, Bianca Frauscher2, Annika Wahlström4, Marcus Ståhlman4, Michael Trauner5, Florian Grahammer6, Tobias B Huber7, Karin Wagner8, Alexander R Rosenkranz2, Hanns-Ulrich Marschall4, Peter Fickert9. 1. Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria. 2. Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Austria. 3. Department of Pathology, Medical University of Graz, Austria. 4. Sahlgrenska Academy, Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden. 5. Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria. 6. Department of Medicine IV, Medical Center and Faculty of Medicine, University of Freiburg, Germany. 7. 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. 8. Core Facility Molecular Biology, Center for Medical Research, Medical University Graz, Graz, Austria. 9. 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.
Abstract
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. LAY SUMMARY: 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.
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: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. CONCLUSION: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. LAY SUMMARY: 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 acidnorUDCA 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: Zoltan V Varga; Katalin Erdelyi; Janos Paloczi; Resat Cinar; Zsuzsanna K Zsengeller; Tony Jourdan; Csaba Matyas; Balazs Tamas Nemeth; Adrien Guillot; Xiaogang Xiang; Adam Mehal; György Haskó; Isaac E Stillman; Seymour Rosen; Bin Gao; George Kunos; Pal Pacher Journal: Hepatology Date: 2018-10 Impact factor: 17.425
Authors: Ahmed Ghallab; Ute Hofmann; Selahaddin Sezgin; Nachiket Vartak; Reham Hassan; Ayham Zaza; Patricio Godoy; Kai Markus Schneider; Georgia Guenther; Yasser A Ahmed; Aya A Abbas; Verena Keitel; Lars Kuepfer; Steven Dooley; Frank Lammert; Christian Trautwein; Michael Spiteller; Dirk Drasdo; Alan F Hofmann; Peter L M Jansen; Jan G Hengstler; Raymond Reif Journal: Hepatology Date: 2018-11-19 Impact factor: 17.425