title: MicroRNA-21 Mediates Angiotensin II-Induced Liver Fibrosis by Activating NLRP3 Inflammasome/IL-1β Axis via Targeting Smad7 and Spry1.
abstract: Angiotensin II (AngII), a vasoconstrictive peptide of the renin-angiotensin system (RAS), promotes hepatic fibrogenesis and induces microRNA-21(mir-21) expression. Angiotensin-(1-7) [Ang-(1-7)] is a peptide of the RAS, which attenuates liver fibrosis. Recently, it was reported that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome participated in liver fibrosis. However, it remains unclear how mir-21 mediates AngII-induced NLRP3 inflammasome activation. We investigate the role of AngII-induced mir-21 in the regulation of NLRP3 inflammasome/IL-1β axis in liver fibrosis.
  
  
  
  In vivo, circulating mir-21 was upregulated in patients with liver fibrosis and was positively correlated with liver fibrosis and oxidation. Treatment with Ang-(1-7) inhibited mir-21, NLRP3 inflammasome, and liver fibrosis after bile duct ligation (BDL) or AngII infusion. Inhibition of mir-21 suppressed the Smad7/Smad2/3/NOX4, Spry1/ERK/NF-κB pathway, NLRP3 inflammasome, and liver fibrosis induced by AngII infusion. In vitro, AngII upregulated mir-21 expression via targeting Smad7 and Spry1 in primary hepatic stellate cells (HSCs). In contrast, Ang-(1-7) suppressed mir-21 expression and oxidation induced by AngII. Overexpression of mir-21 promoted oxidation, and collagen production enhanced the effect of AngII on NLRP3 inflammasome activation via the Spry1/ERK/NF-κB, Smad7/Smad2/3/NOX4 pathways. However, downregulation of mir-21 exerted the opposite effects. Innovation and Conclusions: Mir-21 mediates AngII-activated NLRP3 inflammasome and resultant HSC activation via targeting Spry1 and Smad7. Ang-(1-7) protected against BDL or AngII infusion-induced hepatic fibrosis and inhibited mir-21 expression. Antioxid. Redox Signal. 27, 1-20.
authors: 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors: Zuo-Wei
authors: ZW
authors: Ning
authors: 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors: Xiao-Ying
authors: XY
authors: Luo
authors: 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors: Guo-Zhen
authors: GZ
authors: Wang
authors: 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors: Yang
authors: Y
authors: Li
authors: 2 Department of Respiratory Diseases, Southern Medical University , Guangzhou, China .
authors: Miao-Xia
authors: MX
authors: Pan
authors: 3 Department of Emergency Medicine, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors: Ren-Qiang
authors: RQ
authors: Yang
authors: 3 Department of Emergency Medicine, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors: Xu-Guang
authors: XG
authors: Ling
authors: 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors: Shan
authors: S
authors: Huang
authors: 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors: Xiao-Xin
authors: XX
authors: Ma
authors: 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors: Si-Yi
authors: SY
authors: Jin
authors: 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors: Dan
authors: D
authors: Wang
authors: 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China .|4 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, China .
authors: Xu
authors: X
authors: Li
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins; D035683:MicroRNAs / Q000235:genetics*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D010750:Phosphoproteins; D051381:Rats; D051906:Smad7 Protein / Q000378:metabolism
chemical_list: C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; C524940:MIRN21 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D010750:Phosphoproteins; C497806:SMAD7 protein, human; C486055:SPRY1 protein, human; D051906:Smad7 Protein; D000804:Angiotensin II
keywords: NLRP3 inflammasome; angiotensin II; angiotensin-(1-7); liver fibrosis; microRNA 21; reactive oxygen species