MicroRNA-21 Mediates Angiotensin II-Induced Liver Fibrosis by Activating NLRP3 Inflammasome/IL-1β Axis via Targeting Smad7 and Spry1

Abstract

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.

MiR‐21‐5p regulates mycobacterial survival and inflammatory responses by targeting Bcl‐2 and TLR4 in Mycobacterium tuberculosis‐infected macrophages

“…For example, Ning et al . reported that circulating miR‐21 was up‐regulated in the serum of patients with liver fibrosis and was positively associated with liver fibrosis and oxidation. Loboda et al .…”

“…More and more studies validated that microRNA-21-5p (miR-21-5p) is implicated with infectious or inflammatory diseases. For example, Ning et al [8] reported that circulating miR-21 was up-regulated in the serum of patients with liver fibrosis and was positively associated with liver fibrosis and oxidation. Loboda et al [9] demonstrated that miR-21 plays a dynamic role in inflammatory responses and accelerates organ failure and fibrosis.…”

Inflammasomes and their roles in the pathogenesis of viral hepatitis and their related complications: An updated systematic review

“…Additionally, there is some evidence, which suggests the roles of inflammasomes in the induction of liver fibrosis and HCC. Ning and colleagues reported that microRNA-21 activates NLRP3 inflammasome and then hepatic stellate cells (HSCs) in angiotensin II dependent manner [65]. Angiotensin II and HSCs are the main responsible parameters involved in the fibrosis of the liver [66,67].…”

The Role of MicroRNA-21 and Autophagy in Liver Fibrosis

“…miR-21 has been shown to promote fibro genesis in muscles and various organs including heart, kidneys, lungs and liver [15]. In liver it induces fibrosis by activating hepatic stellate cells (HSC) [16]. Recently, Ning Zuo-Wei et al (2017) showed that over expression of mir-21 promotes oxidation, increases in collagen production and to have profound effect on angiotensin activation via Spry1/ERK/NF-κB, Smad7/Smad2/3/NOX4 pathways and its down regulation exerted the opposite effects [16,17].…”

“…In liver it induces fibrosis by activating hepatic stellate cells (HSC) [16]. Recently, Ning Zuo-Wei et al (2017) showed that over expression of mir-21 promotes oxidation, increases in collagen production and to have profound effect on angiotensin activation via Spry1/ERK/NF-κB, Smad7/Smad2/3/NOX4 pathways and its down regulation exerted the opposite effects [16,17]. Our article in PNAS, showed the miR-21 KO mice have reduced tumorigenic activity in multistage murine skin carcinogenesis model [18], indicating down regulation of miRNA could have therapeutic role in cancer therapy [18].…”