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.
Highlights
Implicated in renal and pulmonary fibrosis[9,10,11,12]
We demonstrate for the first time that the KCa3.1 channel is upregulated in hepatocytes with increasing liver fibrosis, while its absence or inhibition aggravates liver fibrosis
A recent histopathological study based on stainings of only a few fibrotic liver samples reported that these channels are upregulated in hepatic fibrosis, and the channels might be located in activated HSC14
Summary
Implicated in renal and pulmonary fibrosis[9,10,11,12]. KCa3.1 deficiency in mice blunted renal fibrosis[13], and the KCa3.1 inhibitor TRAM-34 was shown to suppress fibrogenic properties of myofibroblasts in vitro[14]. The pathomechanistic roles of KCa3.1 in liver fibrosis especially in experimental studies and in human situation remains unclear, especially in regards to the potential effect of the channel on the high hepatic regenerative potential compared to other parenchymal organs. KCa3.1 deficient mice are characterized by a sizable splenomegaly, which is linked to KCa3.1’s well-established effect on erythrocyte volume regulation[15]. We hypothesized pathomechanistic roles of KCa3.1 in liver injury and fibrosis and tested whether genetic deficiency or pharmacological blockade alters fibrotic remodelling and expression of profibrotic mediators in experimental rodent models
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