title: Angiotensin(1-7) attenuated Angiotensin II-induced hepatocyte EMT by inhibiting NOX-derived H2O2-activated NLRP3 inflammasome/IL-1β/Smad circuit.
abstract: 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.
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Zhang
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xiao-Xin
authors.initials: XX
authors.lastname: Ma
authors.affiliation: Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Wen-Yong
authors.initials: WY
authors.lastname: Zhang
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Si-Yi
authors.initials: SY
authors.lastname: Jin
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Zhang
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: mylx99@163.com.
authors.forename: Xu
authors.initials: X
authors.lastname: Li
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology / Q000502:physiology*; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D000074663:NADPH Oxidase 4 / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D017208:Rats, Wistar; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D010446:Peptide Fragments; D051785:Smad Proteins; D000804:Angiotensin II; D000803:Angiotensin I; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; C118790:angiotensin I (1-7)
keywords: Angiotensin II; Angiotensin-(1–7); Epithelial-mesenchymal transition; Hepatocyte; Liver fibrosis; NADPH oxidase; NLRP3 inflammasome; Reactive oxygen species