Abstract
Acid‐sensing ion channel 1a (ASIC1a) allows Na+ and Ca2+ flow into cells. It is expressed during inflammation, in tumour and ischaemic tissue, in the central nervous system and non‐neuronal injury environments. Endoplasmic reticulum stress (ERS) is caused by the accumulation of misfolded proteins that interferes with intracellular calcium homoeostasis. Our recent reports showed ASIC1a and ERS are involved in liver fibrosis progression, particularly in hepatic stellate cell (HSC) activation. In this study, we investigated the roles of ASIC1a and ERS in activated HSC. We found that ASIC1a and ERS‐related proteins were up‐regulated in carbon tetrachloride (CCl4)‐induced fibrotic mouse liver tissues, and in patient liver tissues with hepatocellular carcinoma with severe liver fibrosis. The results show silencing ASIC1a reduced the expression of ERS‐related biomarkers GRP78, Caspase12 and IREI‐XBP1. And, ERS inhibition by 4‐PBA down‐regulated the high expression of ASIC1a induced by PDGF, suggesting an interactive relationship. In PDGF‐induced HSCs, ASIC1a was activated and migrated to the cell membrane, leading to extracellular calcium influx and ERS, which was mediated by PI3K/AKT pathway. Our work shows PDGF‐activated ASIC1a via the PI3K/AKT pathway, induced ERS and promoted liver fibrosis progression.
Highlights
Acid‐sensing ion channels (ASICs) are members of the degenerin/ epithelial sodium channel family, acting as sensors for extracellular protons distributed in the nervous system and many non‐neuronal cells.[1-3]
We found that ASIC1a expression significantly decreased after silencing PI3K/AKT, suggesting this pathway up‐regulates the activity of the ASIC1a membrane channel (Figure 4D)
Our results demonstrate ASIC1a and Endoplasmic reticulum stress (ERS)‐related proteins were up‐ regulated in CCl4‐induced fibrotic mouse liver tissues, PDGF‐acti‐ vated hepatic stellate cell (HSC) and patient samples
Summary
Acid‐sensing ion channels (ASICs) are members of the degenerin/ epithelial sodium channel family, acting as sensors for extracellular protons distributed in the nervous system and many non‐neuronal cells.[1-3]. The endoplasmic reticulum (ER) is a complex and key organ‐ elle for protein folding, and lipid and carbohydrate metabolism.[15] It is an important Ca2+ storage station that regulates intra‐ cellular Ca2+ signalling that affects many signalling pathways.[16-20]. Aissouni et al and Bo Duan et al showed that PI3K/Akt signalling affects ASIC1a expression and activity via membrane transduction in neurons.[33,34]. This has not been reported in liver fibrosis or HSCs. ERS is involved in the pathogenesis of liver fibrosis, where it activates fat generation transcription factor, triggers inflammation and fibrosis and promotes fatty liver and liver fibrosis.[35,36]. Given that ERS and ASIC1a both play roles in liver fibrosis patho‐ genesis, we analysed their effects on HSC activation and prolifer‐ ation, and looked at possible signalling pathways associated with disease states
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