title: The calcium-activated potassium channel KCa3.1 is an important modulator of hepatic injury.
abstract: The calcium-activated potassium channel KCa3.1 controls different cellular processes such as proliferation and volume homeostasis. We investigated the role of KCa3.1 in experimental and human liver fibrosis. KCa3.1 gene expression was investigated in healthy and injured human and rodent liver. Effect of genetic depletion and pharmacological inhibition of KCa3.1 was evaluated in mice during carbon tetrachloride induced hepatic fibrogenesis. Transcription, protein expression and localisation of KCa3.1 was analysed by reverse transcription polymerase chain reaction, Western blot and immunohistochemistry. Hemodynamic effects of KCa3.1 inhibition were investigated in bile duct-ligated and carbon tetrachloride intoxicated rats. In vitro experiments were performed in rat hepatic stellate cells and hepatocytes. KCa3.1 expression was increased in rodent and human liver fibrosis and was predominantly observed in the hepatocytes. Inhibition of KCa3.1 aggravated liver fibrosis during carbon tetrachloride challenge but did not change hemodynamic parameters in portal hypertensive rats. In vitro, KCa3.1 inhibition leads to increased hepatocyte apoptosis and DNA damage, whereas proliferation of hepatic stellate cells was stimulated by KCa3.1 inhibition. Our data identifies KCa3.1 channels as important modulators in hepatocellular homeostasis. In contrast to previous studies in vitro and other tissues this channel appears to be anti-fibrotic and protective during liver injury.
authors.affiliation: Department of Medical Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.|Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Linda
authors.initials: L
authors.lastname: Sevelsted Møller
authors.affiliation: Department of Medical Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.
authors.forename: Annette Dam
authors.initials: AD
authors.lastname: Fialla
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Schierwagen
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Matteo
authors.initials: M
authors.lastname: Biagini
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Liedtke
authors.affiliation: Department of Liver and Biliopancreatic disorders, University of Leuven, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Laleman
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Reul
authors.affiliation: Department of Medical Gastroenterology and Hepatology, Vejle Hospital, Vejle, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Koch Hansen
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Maj
authors.initials: M
authors.lastname: Rabjerg
authors.affiliation: Department of Pharmacology, University of California, Davis, California, USA.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Singh
authors.affiliation: Departament de Producción Animal, Escuela Politécnica Superior, Huesca, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Surra
authors.affiliation: Departamento Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto de Investigación Sanitaria de Aragón (IIS), Universidad de Zaragoza-CIBEROBN, Zaragoza, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Osada
authors.affiliation: Elbe-Elster Klinikum, Krankenhaus Herzberg, Herzberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Reinehr
authors.affiliation: Department of Medical Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.
authors.forename: Ove B Schaffalitzky
authors.initials: OB
authors.lastname: de Muckadell
authors.affiliation: Aragon Institute of Health Science I CS, Zaragoza, Spain.
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
authors.affiliation: Department of Medical Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.|Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D005260:Female; D055166:Hepatic Stellate Cells / Q000502:physiology; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human