Inhibition of ASICs reduces rat hepatic stellate cells activity and liver fibrosis: An in vitro and in vivo study

Abstract

Hepatic fibrosis is a chronic inflammation-associated disease, which is involved in the infiltration of inflammatory cells and releasing of proinflammatory cytokines. In the pathological process, protons are released by damaged cells and acidosis is considered to play a critical role in cell injury. Although the underlying mechanism (s) remain ill-defined, ASICs (acid-sensing ion channels) are assumed to be involved in this process. The diuretic, amiloride, is neuroprotective in models of cerebral ischemia, a property attributable to the inhibition of central ASICs by the drug. However, the effect of inhibition of ASICs by amiloride in the liver fibrotic process remains unclear. We found that amiloride (25, 50, or 100 μM) could restrain acid-induced HSCs at pH6 in vitro. In vivo experiments showed that amiloride could significantly alleviate liver injury, decreasing levels of profibrogenic cytokines, collagen deposition, and reducing pathological tissue damage. In summary, amiloride inhibits hepatic fibrosis in vivo and in vitro, which is probably associated with the downregulation of ASICs.

ASIC1 inhibition impairs the proliferation and migration of pancreatic stellate cells induced by pancreatic cancer cells

“…As shown in Figure 1B, the interaction caused ASIC1 expression increase in a time-dependent manner in both Panc-1 cells and PSCs, meaning that the malignant features of tumor were reinforced. It has been reported that an acidic environment can up-regulate ASIC1 expression in liver cancer cells, hepatic stellate cells and PSCs [10,11], but our results indicates that, besides acidity, pancreatic cancer cells and PSCs can promote ASIC1 expression for each other, despite through an uncertain mechanism.…”

“…ASIC1 belongs to one of proton-gated ion channels, and is mainly expressed in the mammalian nervous system and several digestive system tumors such as pancreatic cancer, gastric cancer, hepatocellular cancer [7][8][9]. Interestingly, ASIC1 expression also occur in hepatic stellate cells and PSCs, and it mediates acidosis-induced fibrosis, a common non-physiological wound-healing process in liver and pancreatic diseases [10,11]. In particular, ASIC1 regulates the acidity-induced epithelial mesenchymal transition (EMT) of pancreatic cancer cells and activation and autophagy of PSCs, and its expression level is inversely correlated with the tumor prognosis, suggesting its targeting value in pancreatic cancer treatment [8,11].…”

ASIC1a inhibits cell pyroptosis induced by acid‐induced activation of rat hepatic stellate cells

“…It is expressed in the mammalian nervous system and other tissues, in which it exerts pathophysiological effects [28]. Our previous studies showed that ASIC1a is highly expressed in hepatic fibrosis rat tissues and platelet‐derived growth factor (PDGF)–BB‐induced HSCs, and ASIC1a channels promote liver fibrosis by increasing intracellular Ca 2+ [10,11]. In our study, RT‐PCR and western blotting data also showed that, under acid stimulation, the ASIC1a channel was open, and HSC‐T6 was activated, thus suggesting an increase in the expression of α‐SMA and collagen‐I.…”

“…A common feature of these conditions is local tissue acidification and lower pH value [9]. Our previous studies showed that ASIC1a was expressed in rat liver and HSCs, and the level of ASIC1a expression was increased in acid‐activated HSCs, whereas blocking ASIC1a slowed the progression of liver fibrosis [10,11].…”

Pharmacology of acid-sensing ion channels – Physiological and therapeutical perspectives

“…Through inhibition of ASIC1a channels, PcTx1 was recently showed to inhibit the signs of progression of rat hepatic fibrosis (Wu et al, 2014). In vivo experiments showed that amiloride could significantly alleviate rat liver injury, and reduce pathological tissue damage (Pan et al, 2014).…”