Angiotensin(1–7) attenuated Angiotensin II-induced hepatocyte EMT by inhibiting NOX-derived H2O2-activated NLRP3 inflammasome/IL-1β/Smad circuit

• Published in: Free radical biology & medicine 2016-08, Vol.97, p.531-543
• Main Authors: Zhang, Li-Li, Huang, Shan, Ma, Xiao-Xin, Zhang, Wen-Yong, Wang, Dan, Jin, Si-Yi, Zhang, Yan-Ping, Li, Yang, Li, Xu
• Format: Article
• Language: English
• Subjects: Angiotensin I - pharmacology; Angiotensin I - physiology; Angiotensin II; Angiotensin II - physiology; Angiotensin-(1–7); Animals; Cells, Cultured; Collagen Type I - genetics; Collagen Type I - metabolism; Epithelial-Mesenchymal Transition; Gene Expression; Hepatocyte; Hepatocytes - physiology; Humans; Hydrogen Peroxide - metabolism; Inflammasomes - metabolism; Interleukin-1beta - metabolism; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver fibrosis; Male; Mice; NADPH oxidase; NADPH Oxidase 4 - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Peptide Fragments - pharmacology; Peptide Fragments - physiology; Rats, Wistar; Reactive oxygen species; Signal Transduction; Smad Proteins - metabolism
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2016.07.014

Epithelial-mesenchymal transition (EMT) is correlated with NAPDH oxidase (NOX)-derived reactive oxygen species (ROS). The ROS-induced NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome is a novel mechanism of EMT. Angiotensin II (AngII) induces EMT by regulating intracellular ROS. Nevertheless, it has not been reported whether AngII could induce hepatocyte EMT. Angiotensin-(1–7) [Ang-(1–7)] can inhibit the effects of AngII via a counter-regulatory mechanism. However, whether Ang-(1–7) attenuated the effects of AngII on hepatocyte EMT remains unclear. The aim of this study was to determine whether Ang-(1–7) attenuated AngII-induced hepatocyte EMT by inhibiting the NOX-derived ROS-mediated NLRP3 inflammasome/IL-1ß/Smad circuit. In vivo, two animal models were established. In the first model, rats were infused AngII. In the second model, Ang-(1–7) was constantly infused into double bile duct ligated (BDL) rats. In vitro, hepatocytes were pretreated with antioxidant, NLRP3 siRNA, NOX4 siRNA, or Ang-(1–7) before exposure to AngII. In vitro, AngII induced hepatocyte EMT, which was inhibited by N-acetylcysteine (NAC), diphenylene iodonium (DPI), and NOX4 siRNA. NLRP3 inflammasome, which was activated by hydrogen peroxide (H2O2), mediated AngII-induced hepatocyte EMT. Ang-(1–7) suppressed AngII-induced EMT by inhibiting the NOX-derived H2O2-activated NLRP3 inflammasome/IL-1ß/Smad circuit. In vivo, infusion of AngII induced activation of H2O2-correlated NLRP3 inflammasome in rat livers and accumulation of α-collagen I (Col1A1) in hepatocytes. Infusion of Ang-(1–7) alleviated BDL-induced liver fibrosis and inhibited the expression of Col1A1 and the activation of NLRP3 inflammasome in hepatocytes. Ang-(1–7) attenuated AngII-induced hepatocyte EMT by inhibiting the NOX-derived H2O2-activated NLRP3 inflammasome/IL-1ß/Smad circuit. [Display omitted] •Ang II activates NLRP3 inflammasome mediated by NOX-derived H2O2 in hepatocytes.•Ang II initiates hepatocyte EMT by activating the NOX-derived H2O2-mediated NLRP3 inflammasome/IL-1β/Smad circuit.•Ang-(1–7) attenuates Ang II-induced hepatocyte EMT by inhibiting NLRP3 inflammasome activation.