Stage-dependent effects of systemic ASBT inhibition in a cholestasis-induced cholemic nephropathy mouse model
Year: 2025
Type: article
Abstract: Background & Aims: Cholemic nephropathy (CN) is a severe complication of liver diseases associated with cholestasis and represents an unmet medical need. Recently, we identified the molecular mechanism of CN and showed that the systemic apical sodium-dependent bile acid transporter inhibitor (ASBTi) AS0369 prevented CN in mice. However, it is not clear if ASBTi is effective in a therapeutic rather than a preventive setting. Methods: AS0369 was administered daily for 4 weeks to bile duct-ligated (BDL) mice at four CN stages: (1) early stage with proximal tubular epithelial cell (pTEC) death (BDL-day 3); (2) inflammation, leaky peritubular capillaries, and tubular dilatation (BDL-day 21); (3) fibrosis (BDL-day 42); and (4) advanced stage with glomerular cysts (BDL-day 63). Disease progression was evaluated by biochemical, histopathological, and RNA-sequencing analysis. Results: = 0.005) by the ASBTi. RNA-sequencing revealed that ASBTi attenuated BDL-induced gene deregulation at all stages, with a larger effect size at early stages. Conclusions: Early systemic ASBTi therapy, initiated at the onset of pTEC death, provides the greatest therapeutic benefit. Nonetheless, even at later stages, ASBTi can ameliorate features of advanced CN. Impact and implications: This study demonstrates that systemic inhibition of the apical sodium-dependent bile acid transporter (ASBTi) alleviates cholemic nephropathy across disease stages in a bile duct ligation mouse model. The greatest benefit was achieved when treatment was initiated early, coinciding with proximal tubular epithelial cell death, but even advanced features such as glomerular cysts were partially reversed. These findings highlight ASBTi as a promising therapeutic strategy for cholemic nephropathy, addressing a major unmet need in cholestatic liver disease. By targeting bile acid accumulation and related injury pathways, ASBTi may improve renal outcomes and broaden treatment options in affected patients.
Source: JHEP Reports
Authors: Ahmed Ghallab, Maiju Myllys, Daniela González, Adrian Friebel, Zaynab Hobloss, Reham Hassan, Hannah Schmidt, Qasim Siddiqui, Deng Zhipeng, Rama Hendawi, Brigitte Begher-Tibbe, Joerg Reinders, Katharina Derksen, Ute Hofmann, Julia C. Duda, Lucia Ameis, Kathrin Möllenhoff, Abdellatief Seddek, Noha Abdelmageed, Ellen Strängberg, Peter Åkerblad, Mihael Vucur, Tom Luedde, Guido Stirnimann, Matthias Schwab, Tahany Abbas, Benedikt Hild, Hartmut Schmidt, Saul J. Karpen, Benedikt Simbrunner, Mattias Mandorfer, Jörg Rahnenführer, Karolina Edlund, Stefan Hoehme, Michael Trauner, Paul A. Dawson, Erik Lindström, Jan G. Hengstler
Institutions: South Valley University, TU Dortmund University, Leibniz Research Centre for Working Environment and Human Factors, Leipzig University, Essen University Hospital, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, University of Cologne, Sohag University, Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, University of Bern, University Hospital of Bern, Virginia Commonwealth University, Medical University of Vienna, Emory University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,110
Awards: LiSyM-Krebs - Phase II - Verbundprojekt: SMART-NAFLD - Ein systemmedizinischer Ansatz zur Früherkennung und Prävention des hepatozellulären Karzinoms bei Nicht-Alkoholischer Fettlebererkrankung - Teilprojekt C, Progression von NAFLD über NASH zu HCC: Mechanismen der Transitionen von Krankheitsstadien und Identifikation geeigneter Zeitfenster für therapeutische Interventionen, G1792653913, GRK 2624: Biostatistische Methoden für hochdimensionale Daten in der Toxikologie, G3398130443, Funktionelles Imaging zur Erforschung eines bisher nicht berücksichtigten Mechanismus der ParacetamolHepatotoxizität, LiSyM-Krebs - Phase II - Verbundprojekt: C-TIP-HCC - Mechanismus-basiertes Multiskalenmodell zur Dissektion des Tipping Points von Leberzirrhose zu hepatozellulärem Karzinom - Teilprojekt I, G599149724, LiSyM-Krebs - Phase I - Verbundprojekt: SMART-NAFLD - Ein systemmedizinischer Ansatz zur Früherkennung und Prävention des hepatozellulären Karzinoms bei Nicht-Alkoholischer Fettlebererkrankung - Teilprojekt C, G6861959392, Hepatoprotective Mechanisms of Systemic Bile Acid Transporter Inhibitors, G79323727, AcceleRating the Translation of virtual twins towards a pErsonalised Management of fatty lIver patients, LiSyM-Krebs - Phase I - Verbundprojekt: C-TIP-HCC - Mechanismus-basiertes Multiskalenmodell zur Dissektion des tipping points von Leberzirrhose zu Hepatozellulärem Karzinom - Teilprojekt J
OpenAlex ID: W4414475922