Department of Pharmacy, West Branch of The First Affiliated Hospital of University of Science and Technology of China(Anhui Provincial Cancer Hospital), Hefei, 230031, China.
School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
Toxicol Lett. 2019 Jan;300:1-9. doi: 10.1016/j.toxlet.2018.10.003. Epub 2018 Oct 3.
It is well known that the diabetes mellitus complicates liver fibrosis with high morbidity, and Acid-sensing ion Channel 1a (ASIC1a) plays an important role in the development of diabetes and liver fibrosis. However, the underlying mechanism about how diabetes influences the progression of liver fibrosis remains unclear. This study was to investigate the relationship between autophagy and ASIC1a in the process of liver fibrosis under hyperglycemia. Interestingly, our study showed that the autophagy was elevated in the livers from diabetes combined with liver fibrosis double model in vivo and also in rat hepatic stellate cell line HSC-T6 after stimulation with high glucose and platelet-derived growth factor (PDGF) in vitro, and this response could be attenuated by treatment with ASIC1a nonspecific inhibitor Amiloride or specific ShRNA for ASIC1a. Furthermore, inhibition of autophagy treated with 3-MA significantly attenuated HSC-T6 activation and proliferation. Mechanistically, CaMKKβ/ERK pathway was activated in HSC-T6 after stimulation with high glucose and PDGF, and could be suppressed by Amiloride. Collectively, we concluded that autophagy induced by ASIC1a contributes to HSC-T6 activation, which ing pathway.
众所周知，糖尿病会使肝纤维化复杂化，发病率很高，酸感应离子通道 1a（ASIC1a）在糖尿病和肝纤维化的发展中起重要作用。然而，糖尿病如何影响肝纤维化进展的潜在机制尚不清楚。本研究旨在探讨高血糖状态下自噬与 ASIC1a 在肝纤维化过程中的关系。有趣的是，我们的研究表明，在糖尿病合并肝纤维化双模型体内以及在高糖和血小板衍生生长因子（PDGF）刺激的大鼠肝星状细胞系 HSC-T6 中，自噬水平升高，而这种反应可以被 ASIC1a 非特异性抑制剂阿米洛利或 ASIC1a 的特异性 ShRNA 减弱。此外，用 3-MA 抑制自噬可显著减弱 HSC-T6 的激活和增殖。在机制上，高糖和 PDGF 刺激后 HSC-T6 中激活钙调蛋白激酶β/ERK 通路，阿米洛利可抑制该通路。总之，我们得出结论，ASIC1a 诱导的自噬有助于 HSC-T6 的激活，这可能与 CaMKKβ/ERK 通路有关。
