title: Angiotensin-(1-7) Improves Liver Fibrosis by Regulating the NLRP3 Inflammasome via Redox Balance Modulation.
abstract: Angiotensin II (Ang II) aggravates hepatic fibrosis by inducing NADPH oxidase (NOX)-dependent oxidative stress. Angiotensin-(1-7) [Ang-(1-7)], which counter-regulates Ang II, has been evidenced to protect against hepatic fibrosis. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, being activated by reactive oxygen species (ROS), is identified as a novel mechanism of liver fibrosis. However, whether the NLRP3 inflammasome involves in regulation of Ang II-induced hepatic fibrosis remains unclear. This study investigates the different effects of the Ang II and Ang-(1-7) on collagen synthesis by regulating the NLRP3 inflammasome/Smad pathway via redox balance modulation.
  
  
  
  In vivo, Ang-(1-7) improved bile duct ligation-induced hepatic fibrosis, reduced H2O2 content, protein levels of NOX4, and the NLRP3 inflammasome, whereas it increased glutathione (GSH) and nuclear erythroid 2-related factor 2 (Nrf2) antioxidant response element (ARE). In vitro, Ang II treatment elevated NOX4 protein expression and ROS production in hepatic stellate cells (HSCs), whereas it inhibited GSH and Nrf2-ARE, resulting in the activation of the NLRP3 inflammasome in the mitochondria of HSCs. NLRP3 depletion inhibited Ang II-induced collagen synthesis. Furthermore, Ang II increased NLRP3 and pro-IL-1β levels by activating the Toll-like receptor 4 (TLR4)/MyD88/NF-κB pathway. Treatment with antioxidants, NOX4 small interference RNA (siRNA), or Nrf2 activator inhibited Ang II-induced NLRP3 inflammasome activation and collagen synthesis. In contrast, the action of Ang-(1-7) opposed the effects of Ang II.
  
  
  
  Ang-(1-7) improved liver fibrosis by regulating NLRP3 inflammasome activation induced by Ang II-mediated ROS via redox balance modulation. Antioxid. Redox Signal. 24, 795-812.
authors.affiliation: 1 State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, the Southern Medical University , Guangzhou, China .|2 Department of Emergency Medicine, Nanfang Hospital, the Southern Medical University , Guangzhou, China .
authors.forename: Shuang-Ming
authors.initials: SM
authors.lastname: Cai
authors.affiliation: 2 Department of Emergency Medicine, Nanfang Hospital, the Southern Medical University , Guangzhou, China .
authors.forename: Ren-Qiang
authors.initials: RQ
authors.lastname: Yang
authors.affiliation: 2 Department of Emergency Medicine, Nanfang Hospital, the Southern Medical University , Guangzhou, China .
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: 3 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, the Southern Medical University , Guangzhou, China .
authors.forename: Zuo-Wei
authors.initials: ZW
authors.lastname: Ning
authors.affiliation: 2 Department of Emergency Medicine, Nanfang Hospital, the Southern Medical University , Guangzhou, China .
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Zhang
authors.affiliation: 4 Department of Emergency Medicine, the Military General Hospital of Beijing PLA , Beijing, China .
authors.forename: Gao-Su
authors.initials: GS
authors.lastname: Zhou
authors.affiliation: 3 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, the Southern Medical University , Guangzhou, China .
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.affiliation: 2 Department of Emergency Medicine, Nanfang Hospital, the Southern Medical University , Guangzhou, China .
authors.forename: Da-Huan
authors.initials: DH
authors.lastname: Li
authors.affiliation: 5 Department of Respiratory Diseases, Nanfang Hospital, the Southern Medical University , Guangzhou, China .
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 5 Department of Respiratory Diseases, Nanfang Hospital, the Southern Medical University , Guangzhou, China .
authors.forename: Miao-Xia
authors.initials: MX
authors.lastname: Pan
authors.affiliation: 1 State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, the Southern Medical University , Guangzhou, China .|3 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, the Southern Medical University , Guangzhou, China .
authors.forename: Xu
authors.initials: X
authors.lastname: Li
mesh_terms: D000803:Angiotensin I / Q000008:administration & dosage / Q000502:physiology*; D000818:Animals; D061745:Antioxidant Response Elements; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000502:physiology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000008:administration & dosage / Q000502:physiology*; D055503:Protein Multimerization; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C526316:CCN2 protein, rat; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D058847:Inflammasomes; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D051785:Smad Proteins; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D055513:Connective Tissue Growth Factor; D000803:Angiotensin I; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; C118790:angiotensin I (1-7)