Activation of BK Channels Prevents Hepatic Stellate Cell Activation and Liver Fibrosis Through the Suppression of TGFβ1/SMAD3 and JAK/STAT3 Profibrotic Signaling Pathways
Activation of BK Channels Prevents Hepatic Stellate Cell Activation and Liver Fibrosis Through the Suppression of TGFβ1/SMAD3 and JAK/STAT3 Profibrotic Signaling Pathways
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BK 通道的激活通过抑制 TGF beta 1/SMAD3 和 JAK/STAT3 促纤维化信号通路来防止肝星状细胞激活和肝纤维化
DOI：
10.3389/fphar.2020.00165
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发表时间：
2020-03-06
影响因子：
5.6
通讯作者：
Hou, Shangwei
中科院分区：
文献类型：
--
作者：
Yang, Linli;Han, Bo;Hou, Shangwei
大电导和Ca 2+激活的K+（BK）通道在人肝星状细胞（HSC）中表达，其中它们在正常的肝微循环中起作用，以及通过调节激活的HSC中的收缩性在肝硬化的门静脉高压中起作用。然而，BK通道活性是否对异常HSC活化和肝纤维化发挥保护作用尚不清楚。在这里，我们报告说，BK通道表达在激活的原代大鼠HSC以及在人类HSC系。此外，从活化的HSC记录的全细胞K+电流显着增加暴露于rottlerin，BK通道特异性激活剂，但被抑制治疗与BK通道特异性抑制剂，paxilline，这表明BK通道在活化的HSC的功能。BK通道成孔α亚基KCNMA 1的过表达而非下调导致活化HSC中迁移和胶原表达减少。因此，罗特勒林治疗抑制了体外和体内CCl 4诱导的肝纤维化中的纤维化细胞功能。微阵列和途径分析，结合荧光素酶报告基因测定和蛋白质印迹，进一步表明，rottlerin治疗导致促纤维化TGF β 1/SMAD 3和JAK/STAT 3信号通路的显着下调，在体外和体内。我们的研究结果不仅将BK通道功能与促纤维化信号通路联系起来，而且还提供了证据表明BK通道激活代表了治疗肝纤维化的有前途的治疗策略。
Large-conductance and Ca2+-activated K+ (BK) channels are expressed in human hepatic stellate cells (HSCs), where they have roles in normal hepatic microcirculation, as well as in portal hypertension in liver cirrhosis through the regulation of contractility in activated HSCs. Nevertheless, whether BK channel activity exerts protective effects against aberrant HSC activation and hepatic fibrosis is unknown. Here, we report that BK channels are expressed in activated primary rat HSCs as well as in a human HSC line. Moreover, whole-cell K+ currents recorded from activated HSCs were markedly increased by exposure to rottlerin, a BK channel-specific activator, but were inhibited by treatment with the BK channel-specific inhibitor, paxilline, suggesting that BK channels are functional in activated HSCs. Overexpression but not downregulation of the BK channel pore-forming alpha subunit, KCNMA1, led to reduced migration and collagen expression in activated HSCs. Consistently, rottlerin treatment suppressed the fibrogenic cell function both in vitro and in CCl4-induced liver fibrosis in vivo. Microarray and pathway analysis, combined with a luciferase reporter assay and western blotting, further showed that rottlerin treatment led to a significant downregulation of the profibrotic TGF beta 1/SMAD3 and JAK/STAT3 signaling pathways, both in vitro and in vivo. Our findings not only link BK channel function to profibrotic signaling pathways, but also provide evidence that BK channel activation represents a promising therapeutic strategy for the treatment of liver fibrosis.