Inhibition of acid-sensing ion channel 1a in hepatic stellate cells attenuates PDGF-induced activation of HSCs through MAPK pathway

Abstract

Acid-sensing ion channels (ASICs), a group of Na(+)-selective and Ca(2+)-permeant ligand-gated cation channels, can be transiently activated by extracellular acid. Among seven subunits of ASICs, acid-sensing ion channel 1a (ASIC1a), which is responsible for Ca(2+) transportation, is elevated in response to inflammation, tumor, and ischemic injury in central nervous system and non-neuronal tissues. In this study, we demonstrated for the first time the presence of ASIC1a in rat liver and hepatic stellate cells (HSCs). Furthermore, the expression of ASIC1a was increased in primary HSCs and liver tissues of CCl4-treated rats, suggesting that ASIC1a may play certain role in liver fibrosis. Interestingly, we identified that the level of ASIC1a was significantly elevated in response to platelet-derived growth factor (PDGF) induction in a time- and dose-dependent manner. It was also established that Ca(2+)-transporting ASIC1a was involved in acid-induced injury of different cell types. Moreover, inhibition or silencing of ASIC1a was able to inhibit PDGF-induced pro-fibrogenic effects of activated rat HSCs, including cell activation, de novo synthesis of extracellular matrix components through mitogen-activated protein kinase signaling pathway. Collectively, our studies identified that ASIC1a was expressed in rat liver and HSCs and provided a strong evidence for the involvement of the ASIC1a in the progression of hepatic fibrosis.

The adenosine monophosphate–activated protein kinase—vacuolar adenosine triphosphatase–pH axis: A key regulator of the profibrogenic phenotype of human hepatic stellate cells

“…Bafilomycin acts by inhibiting proton flow through the v‐ATPase pump, although after 48 hours of treatment an acute acid load is still able to induce an increment in pH. This suggests that other pumps, such as the Na + /H + exchanger, are still active and exert a compensatory effect for the lack of active v‐ATPase . In contrast, KM91104 is a weaker inhibitor than bafilomycin because it specifically targets the interaction between v‐ATPase subunits a3 and B2, without interfering with the pump activity.…”

“…This suggests that other pumps, such as the Na 1 / H 1 exchanger, are still active and exert a compensatory effect for the lack of active v-ATPase. (3,33,34) In contrast, KM91104 is a weaker inhibitor than bafilomycin because it specifically targets the interaction between v-ATPase subunits a3 and B2, (22) without interfering with the pump activity.…”

Platelet-Derived Growth Factor and Transforming Growth Factor β1 Regulate ARDS-Associated Lung Fibrosis Through Distinct Signaling Pathways

“…PDGF binds to its receptor (a receptor tyrosine kinase (RTK)) on the ligand binding pocket located within the second and third immunoglobulin domains [16,17]. Upon activation by PDGF, the receptor was phosphorylated to activate downstream signaling cascades, among which mitogen-activated protein kinase (MAPK) has been shown to regulate fibroblast growth [18][19][20][21][22][23][24][25].…”

Analysis of Polymorphism and Expression Profile of ASIC1 and IL-6 Genes in Patients with Gastric Cancer

“…Studies by Yifeng et al, (2011) show that a low-level expression of ASIC is related to the remedy of ischemic-brain attack. According to a report by Wu et al, (2014) high level of expression of ASIC is related to the progression of cancer. Previous studies had observed significant differences in the frequencies of IL-6 polymorphism in the−174 G/C loci in breast cancer, uterine leiomyosarcoma, and multiple myeloma.…”