Alamandine attenuates hepatic fibrosis by regulating autophagy induced by NOX4-dependent ROS. Issue 7 (9th April 2020)

• Record Type: Journal Article
• Authors: Huang, Yun; Li, Yang; Lou, Anni; Wang, Guo zhen; Hu, Ye; Zhang, Yijie; Huang, Weichang; Wang, Jun; Li, Yue; Zhu, Xintao; Chen, Tingting; Lin, Jiayi; Meng, Ying; Li, Xu
• Is Part Of: Clinical science. Volume 134:Issue 7(2020)
• Page Start: 853
• Page End: 869
• Publication Date: 2020-04-09
• Subjects: Alamandine -- Angiotensin II -- Autophagy -- Hepatic fibrosis -- NADPH oxidase -- Oxidative stress; Medicine -- Periodicals; Biochemistry -- Periodicals; 616
• DOI: 10.1042/CS20191235
• Languages: English
• ISSNs: 0143-5221

Abstract

Abstract: Angiotensin II (Ang II) has been reported to aggravate hepatic fibrosis by inducing NADPH oxidase (NOX)-dependent oxidative stress. Alamandine (ALA) protects against fibrosis by counteracting Ang II via the MAS-related G-protein coupled (MrgD) receptor, though the effects of alamandine on hepatic fibrosis remain unknown. Autophagy activated by reactive oxygen species (ROS) is a novel mechanism of hepatic fibrosis. However, whether autophagy is involved in the regulation of Ang II-induced hepatic fibrosis still requires investigation. We explored the effect of alamandine on hepatic fibrosis via regulation of autophagy by redox balance modulation. In vivo, alamandine reduced CCl4 -induced hepatic fibrosis, hydrogen peroxide (H2 O2 ) content, protein levels of NOX4 and autophagy impairment. In vitro, Ang II treatment elevated NOX4 protein expression and ROS production along with up-regulation of the angiotensin converting enzyme (ACE)/Ang II/Ang II type 1 receptor (AT1R) axis. These changes resulted in the accumulation of impaired autophagosomes in hepatic stellate cells (HSCs). Treatment with NOX4 inhibitor VAS2870, ROS scavenger N-acetylcysteine (NAC), and NOX4 small interfering RNA (siRNA) inhibited Ang II-induced autophagy and collagen synthesis. Alamandine shifted the balance of renin–angiotensin system (RAS) toward the angiotensin converting enzyme 2 (ACE2)/alamandine/MrgD axis, and inhibited both Ang II-induced ROS and autophagy activation, leading to attenuation of HSCs migration or collagen synthesis. In summary, alamandine attenuated liver fibrosis by regulating autophagy induced by NOX4-dependent ROS.