MicroRNA-21 Mediates Angiotensin II-Induced Liver Fibrosis by Activating NLRP3 Inflammasome/IL-1β Axis via Targeting Smad7 and Spry1.
MicroRNA-21 Mediates Angiotensin II-Induced Liver Fibrosis by Activating NLRP3 Inflammasome/IL-1β Axis via Targeting Smad7 and Spry1.
复制标题
MicroRNA-21 通过靶向 Smad7 和 Spry1 激活 NLRP3 炎性体/IL-1β 轴介导血管紧张素 II 诱导的肝纤维化
DOI：
10.1089/ars.2016.6669
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发表时间：
2017-07-01
影响因子：
6.6
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Ning ZW;Luo XY;Wang GZ;Li Y;Pan MX;Yang RQ;Ling XG;Huang S;Ma XX;Jin SY;Wang D;Li X
目的：血管紧张素II （AngII）是肾素-血管紧张素系统（RAS）的一种血管收缩肽，促进肝纤维化并诱导microRNA-21（mir-21）的表达。血管紧张素-(1-7)[Ang-(1-7)]是RAS的一种肽，可减轻肝纤维化。最近有报道称，nod样受体家族pyrin domain containing 3 （NLRP3）炎性体参与肝纤维化。然而，尚不清楚mir-21如何介导血管诱导的NLRP3炎性体激活。我们研究了血管诱导的mir-21在调节NLRP3炎性体/IL-1β轴在肝纤维化中的作用。结果：在体内，循环mir-21在肝纤维化患者中上调，并与肝纤维化和氧化呈正相关。Ang-(1-7)治疗可抑制mir-21、NLRP3炎性体和胆管结扎（BDL）或AngII输注后的肝纤维化。抑制mir-21可抑制Smad7/Smad2/3/NOX4、Spry1/ERK/NF-κB通路、NLRP3炎性体和AngII输注诱导的肝纤维化。在体外，AngII通过靶向Smad7和Spry1在原代肝星状细胞（hsc）中上调mir-21的表达。相反，Ang-(1-7)抑制mir-21的表达和AngII诱导的氧化。过表达mir-21促进氧化，胶原生成通过Spry1/ERK/NF-κB、Smad7/Smad2/3/NOX4途径增强AngII对NLRP3炎性体激活的作用。然而，mir-21的下调产生相反的效果。创新和结论：Mir-21通过靶向Spry1和Smad7介导血管激活的NLRP3炎性体和由此产生的HSC激活。Ang-(1-7)可防止BDL或AngII输注诱导的肝纤维化，并抑制mir-21的表达。Antioxid。氧化还原信号，27,1-20。
Aims: 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. Results: 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.