Inhibition of the Renal Apical Sodium Dependent Bile Acid Transporter Prevents Cholemic Nephropathy in Mice with Obstructive Cholestasis.

Bile cast nephropathy Bile duct ligation Cholestasis Intravital imaging Kidney injury

Journal

Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886

Informations de publication

Date de publication:
06 Nov 2023
Historique:
received: 28 03 2023
revised: 06 10 2023
accepted: 23 10 2023
medline: 9 11 2023
pubmed: 9 11 2023
entrez: 8 11 2023
Statut: aheadofprint

Résumé

Cholemic nephropathy (CN) is a severe complication of cholestasis-associated liver diseases, with no specific treatment. We revisited the pathophysiology to identify therapeutic strategies. Cholestasis was induced by bile duct ligation (BDL) in mice. Bile flux in kidneys and livers was visualized by intravital imaging, supported by MALDI-MSI and LC-MS/MS. The effect of AS0369, a systemically bioavailable apical sodium-dependent bile acid transporter (ASBT) inhibitor, was evaluated by intravital imaging, RNA-sequencing, histological, blood, and urine analyses. Translational relevance was assessed by ASBT immunostaining in kidney biopsies of CN patients, analysis of mice with humanized BA spectrum, and by analysis of serum bile acids (BA) and kidney injury molecule (KIM-1) in liver disease and hyperbilirubinemia patients. Proximal tubular epithelial cells (TEC) reabsorbed and enriched BA, leading to oxidative stress and death of proximal TEC, casts in distal tubules and collecting ducts, peritubular capillaries leakiness, and glomerular cysts. Renal ASBT inhibition by AS0369 blocked BA uptake into TEC and prevented kidney injury up to 6 weeks after BDL. Similar results were obtained in mice with humanized BA composition. In advanced liver disease patients, serum BA were the main determinant of KIM-1 levels. ASBT expression in TEC was preserved in biopsies from CN patients, further highlighting the translational potential of targeting ASBT for treatment of CN. BA enrichment in proximal TEC followed by oxidative stress and cell death is an early key event in CN. Inhibiting renal ASBT and consequently BA enrichment in TEC prevents CN and systemically decreases BA concentrations. Cholemic nephropathy (CN) is a severe complication of cholestasis with an unmet clinical need for therapy. We demonstrate that CN is triggered by the renal accumulation of bile acids (BA)- that are considerably increased in the systemic blood. Specifically, the proximal tubular epithelial cells (TEC) of the kidney take up BA via the apical sodium-dependent bile acid transporter (ASBT). We developed a therapeutic compound that blocks ASBT in the kidneys, prevents BA overload in TEC, and almost completely abolished all disease hallmarks in a CN mouse model. Renal ASBT inhibition represents a potential therapeutic strategy for CN patients.

Sections du résumé

BACKGROUND & AIMS OBJECTIVE
Cholemic nephropathy (CN) is a severe complication of cholestasis-associated liver diseases, with no specific treatment. We revisited the pathophysiology to identify therapeutic strategies.
METHODS METHODS
Cholestasis was induced by bile duct ligation (BDL) in mice. Bile flux in kidneys and livers was visualized by intravital imaging, supported by MALDI-MSI and LC-MS/MS. The effect of AS0369, a systemically bioavailable apical sodium-dependent bile acid transporter (ASBT) inhibitor, was evaluated by intravital imaging, RNA-sequencing, histological, blood, and urine analyses. Translational relevance was assessed by ASBT immunostaining in kidney biopsies of CN patients, analysis of mice with humanized BA spectrum, and by analysis of serum bile acids (BA) and kidney injury molecule (KIM-1) in liver disease and hyperbilirubinemia patients.
RESULTS RESULTS
Proximal tubular epithelial cells (TEC) reabsorbed and enriched BA, leading to oxidative stress and death of proximal TEC, casts in distal tubules and collecting ducts, peritubular capillaries leakiness, and glomerular cysts. Renal ASBT inhibition by AS0369 blocked BA uptake into TEC and prevented kidney injury up to 6 weeks after BDL. Similar results were obtained in mice with humanized BA composition. In advanced liver disease patients, serum BA were the main determinant of KIM-1 levels. ASBT expression in TEC was preserved in biopsies from CN patients, further highlighting the translational potential of targeting ASBT for treatment of CN.
CONCLUSIONS CONCLUSIONS
BA enrichment in proximal TEC followed by oxidative stress and cell death is an early key event in CN. Inhibiting renal ASBT and consequently BA enrichment in TEC prevents CN and systemically decreases BA concentrations.
IMPACT AND IMPLICATIONS UNASSIGNED
Cholemic nephropathy (CN) is a severe complication of cholestasis with an unmet clinical need for therapy. We demonstrate that CN is triggered by the renal accumulation of bile acids (BA)- that are considerably increased in the systemic blood. Specifically, the proximal tubular epithelial cells (TEC) of the kidney take up BA via the apical sodium-dependent bile acid transporter (ASBT). We developed a therapeutic compound that blocks ASBT in the kidneys, prevents BA overload in TEC, and almost completely abolished all disease hallmarks in a CN mouse model. Renal ASBT inhibition represents a potential therapeutic strategy for CN patients.

Identifiants

DOI: 10.1016/j.jhep.2023.10.035 PMID: 37939855
pubmed: 37939855
pii: S0168-8278(23)05235-2
doi: 10.1016/j.jhep.2023.10.035
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest AG and JGH declare consulting activities for Albireo Pharma. ES and EL are employees of Albireo Pharma. HUM declares consulting or advisory board activities for Albireo Pharma, Calliditas, Intercept, Mirum and Zealand and lecture fees by Albireo, Intercept and Bayer. SJK declares consulting activities for Albireo Pharma, Hemoshear, Intercept Pharma, and Mirum Pharma; PAD has received research grants from Albireo Pharma. B.S. received travel support from AbbVie and Gilead. TR received grant support from AbbVie, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens and W. L. Gore & Associates; speaking honoraria from Abbvie, Gilead, Intercept/Advanz Pharma, Roche, MSD, W. L. Gore & Associates; consulting/advisory board fee from Abbvie, Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Resolution Therapeutics, Siemens; and travel support from Abbvie, Boehringer Ingelheim, Dr. Falk Pharma, Gilead and Roche. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Collective Acumen, Echosens, Gilead, Ipsen, Takeda, and W. L. Gore & Associates and received travel support from AbbVie and Gilead. MT received speaker fees from BMS, Falk Foundation, Gilead, Intercept, Jannsen, Madrigal, and MSD; he advised for AbbVie, Albireo Pharma, BiomX, Boehringer Ingelheim, Falk Pharma GmbH, Genfit, Gilead, Hightide, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens and Shire. He further received travel grants from AbbVie, Falk, Gilead, Intercept and Jannsen and research grants from Albireo Pharma, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda and UltraGenyx. He is also co-inventor of patents on the medical use of norUDCA filed by the Medical Universities of Graz and Vienna. MS received travel expenses and research support from Agena Bioscience, CED Service GmbH, and ALL Akademie. MS was involved in clinical trials by Green Cross WellBeing Co.Ltd., Gilead Sciences Inc., CORAT Therapeutics GmbH, Agena Bioscience, and HepaRegenix GmbH.

Auteurs

Ahmed Ghallab (A)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany; Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt. Electronic address: ghallab@ifado.de.

Daniela González (D)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Ellen Strängberg (E)

Albireo Pharma, Inc., Boston, MA 02109, USA.

Ute Hofmann (U)

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Auerbachstr. 112, 70376 Stuttgart, Germany.

Maiju Myllys (M)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Reham Hassan (R)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany; Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt.

Zaynab Hobloss (Z)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Lisa Brackhagen (L)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Brigitte Begher-Tibbe (B)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Julia C Duda (JC)

Department of Statistics, TU Dortmund University, 44227 Dortmund, Germany.

Carolin Drenda (C)

Department of Statistics, TU Dortmund University, 44227 Dortmund, Germany.

Franziska Kappenberg (F)

Department of Statistics, TU Dortmund University, 44227 Dortmund, Germany.

Joerg Reinders (J)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Adrian Friebel (A)

Institute of Computer Science & Saxonian Incubator for Clinical Research (SIKT), University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany.

Mihael Vucur (M)

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty at Heinrich-Heine-University, 40225 Dusseldorf, Germany.

Monika Turajski (M)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Abdel-Latief Seddek (AL)

Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt.

Tahany Abbas (T)

Histology Department, Faculty of Medicine, South Valley University, 83523 Qena, Egypt.

Noha Abdelmageed (N)

Department of Pharmacology, Faculty of Veterinary Medicine, Sohag University, 82524 Sohag, Egypt.

Samy A F Morad (SAF)

Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt.

Walaa Morad (W)

Histology Department, Faculty of Medicine, South Valley University, 83523 Qena, Egypt.

Amira Hamdy (A)

Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt.

Wiebke Albrecht (W)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Naim Kittana (N)

Department of Biomedical Sciences, An-Najah National University, P.O. Box 7 Nablus, Palestine.

Mohyeddin Assali (M)

Department of Pharmacy, An-Najah National University, P.O. Box 7 Nablus, Palestine.

Nachiket Vartak (N)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Christoph van Thriel (C)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Ansam Sous (A)

Department of Pharmacy, An-Najah National University, P.O. Box 7 Nablus, Palestine.

Patrick Nell (P)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Maria Villar-Fernandez (M)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Cristina Cadenas (C)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Erhan Genc (E)

MRI Unit, Leibniz Research Centre for Working Environment and Human Factors, Department of Psychology and Neurosciences, Technical University Dortmund, 44139 Dortmund, Germany.

Rosemarie Marchan (R)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Tom Luedde (T)

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty at Heinrich-Heine-University, 40225 Dusseldorf, Germany.

Peter Åkerblad (P)

Albireo Pharma, Inc., Boston, MA 02109, USA.

Jan Mattsson (J)

Albireo Pharma, Inc., Boston, MA 02109, USA.

Hanns-Ulrich Marschall (HU)

Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden.

Stefan Hoehme (S)

Institute of Computer Science & Saxonian Incubator for Clinical Research (SIKT), University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany.

Guido Stirnimann (G)

University Clinic for Visceral Surgery and Medicine, Inselspital University Hospital, University of Bern, 3010 Bern, Switzerland.

Matthias Schwab (M)

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Auerbachstr. 112, 70376 Stuttgart, Germany; Departments of Clinical Pharmacology, and of Biochemistry and Pharmacy, University Tuebingen, 72076 Tuebingen, Germany; Cluster of Excellence iFIT (EXC2180), Image-Guided and Functionally Instructed Tumor Therapies, University of Tuebingen, 69120 Tuebingen, Germany.

Peter Boor (P)

Institute of Pathology and Department of Nephrology, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany.

Kerstin Amann (K)

Department of Nephropathology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany.

Jessica Schmitz (J)

Institute of Pathology, Nephropathology Unit, Hannover Medical School, 30625 Hannover, Germany.

Jan H Bräsen (JH)

Institute of Pathology, Nephropathology Unit, Hannover Medical School, 30625 Hannover, Germany.

Jörg Rahnenführer (J)

Department of Statistics, TU Dortmund University, 44227 Dortmund, Germany.

Karolina Edlund (K)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany.

Saul J Karpen (SJ)

Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, United States.

Benedikt Simbrunner (B)

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Thomas Reiberger (T)

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Mattias Mandorfer (M)

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Michael Trauner (M)

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; Hans Popper Laboratory of Molecular Hepatology, Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Paul A Dawson (PA)

Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, United States.

Erik Lindström (E)

Albireo Pharma, Inc., Boston, MA 02109, USA.

Jan G Hengstler (JG)

Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139 Dortmund, Germany. Electronic address: hengstler@ifado.de.

Classifications MeSH