title: A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways.
abstract: Clinical data strongly indicate that acute kidney injury (AKI) is a critical complication in alcoholic hepatitis, an acute-on-chronic form of liver failure in patients with advanced alcoholic fibrosis. Development of targeted therapies for AKI in this setting is hampered by the lack of an animal model. To enable research into molecular drivers and novel therapies for fibrosis- and alcohol-associated AKI, we aimed to combine carbon tetrachloride (CCl4)-induced fibrosis with chronic intra-gastric alcohol feeding. Male C57BL/6J mice were administered a low dose of CCl4(0.2ml/kg 2× week/6weeks) followed by alcohol intragastrically (up to 25g/kg/day for 3weeks) and with continued CCl4. We observed that combined treatment with CCl4and alcohol resulted in severe liver injury, more pronounced than using each treatment alone. Importantly, severe kidney injury was evident only in the combined treatment group. This mouse model reproduced distinct pathological features consistent with AKI in human alcoholic hepatitis. Transcriptomic analysis of kidneys revealed profound effects in the combined treatment group, with enrichment for damage-associated pathways, such as apoptosis, inflammation, immune-response and hypoxia. Interestingly, Havcr1 and Lcn2, biomarkers of AKI, were markedly up-regulated. Overall, this study established a novel mouse model of fibrosis- and alcohol-associated AKI and identified key mechanistic pathways.
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA.
authors.forename: Shinji
authors.initials: S
authors.lastname: Furuya
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA.
authors.forename: Grace A
authors.initials: GA
authors.lastname: Chappell
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Iwata
authors.affiliation: Laboratory of Veterinary Pathology, Osaka Prefecture University, Osaka, Japan.
authors.forename: Takeki
authors.initials: T
authors.lastname: Uehara
authors.affiliation: Laboratory of Veterinary Pathology, Osaka Prefecture University, Osaka, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kato
authors.affiliation: First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kono
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Ramon
authors.initials: R
authors.lastname: Bataller
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA. Electronic address: irusyn@tamu.edu.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications*; D000818:Animals; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D008103:Liver Cirrhosis / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000431:Ethanol