The calcium-activated potassium channel KCa3.1 is an important modulator of hepatic injury

Linda Maria Sevelsted Møller, Annette Dam Fialla, Robert Schierwagen, Matteo Biagini, Christian Liedtke, Wim Laleman, Sabine Klein, Winfried Reul, Lars Koch Hansen, Maj Rabjerg, Vikrant Singh, Joaquin Surra, Jesus Osada, Roland Reinehr, Ove B Schaffalitzky de Muckadell, Ralf Köhler, Jonel Trebicka

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Abstrakt

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.

OriginalsprogEngelsk
Artikelnummer28770
TidsskriftScientific Reports
Vol/bind6
Antal sider12
ISSN2045-2322
DOI
StatusUdgivet - 29. jun. 2016

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