Abstract
MicroRNA-21 (mir-21) induced by angiotensin II (AngII) plays a vital role in the development of pulmonary fibrosis, and the NLRP3 inflammasome is known to be involved in fibrogenesis. However, whether there is a link between mir-21 and the NLRP3 inflammasome in pulmonary fibrosis is unknown. Angiotensin-converting enzyme 2/angiotensin(1–7) [ACE2/Ang(1–7)] has been shown to attenuate AngII-induced pulmonary fibrosis, but it is not clear whether ACE2/Ang(1–7) protects against pulmonary fibrosis by inhibiting AngII-induced mir-21 expression. This study’s aim was to investigate whether mir-21 activates the NLRP3 inflammasome and mediates the different effects of AngII and ACE2/Ang(1–7) on lung fibroblast apoptosis and collagen synthesis. In vivo, AngII exacerbated bleomycin (BLM)-induced lung fibrosis in rats, and elevated mir-21 and the NLRP3 inflammasome. In contrast, ACE2/Ang(1–7) attenuated BLM-induced lung fibrosis, and decreased mir-21 and the NLRP3 inflammasome. In vitro, AngII activated the NLRP3 inflammasome by up-regulating mir-21, and ACE2/Ang(1–7) inhibited NLRP3 inflammasome activation by down-regulating AngII-induced mir-21. Over-expression of mir-21 activated the NLRP3 inflammasome via the ERK/NF-κB pathway by targeting Spry1, resulting in apoptosis resistance and collagen synthesis in lung fibroblasts. These results indicate that mir-21 mediates the inhibitory effect of ACE2/Ang(1–7) on AngII-induced activation of the NLRP3 inflammasome by targeting Spry1 in lung fibroblasts.
Highlights
We hypothesized that angiotensin-converting enzyme 2 (ACE2)/Ang[1,2,3,4,5,6,7] prevents angiotensin II (AngII)-induced pulmonary fibrosis by inhibiting the expression of mir-21, and that mir-21 mediates the inhibitory effect of ACE2/Ang[1,2,3,4,5,6,7] on AngII-induced-NLRP3 inflammasome activation via the extracellular signal-regulated kinase (ERK)/NF-κB pathway by targeting Spry1 in lung fibroblasts
We have demonstrated that AngII-upregulated mir-21 activates the NLRP3 inflammasome by targeting Spry1, which promoted lung fibroblast collagen synthesis and exacerbated BLM-induced fibrosis
The study’s principal findings are that: [1] mir-21 mediates collagen synthesis by activating the ERK/NF-κB/NLRP3 inflammsome pathway via targeting Spry1 in lung fibroblasts; [2] mir-21 is up-regulated in primary lung fibroblasts treated with AngII and in BLM-induced pulmonary fibrosis; and [3] mir-21 mediates the inhibitory effect of ACE2/Ang[1,2,3,4,5,6,7] on AngII-induced NLRP3 inflammasome activation by targeting Spry1 in lung fibroblasts
Summary
Overexpression of mir-21 activated the NLRP3 inflammasome via the ERK/NF-κB pathway by targeting Spry, resulting in apoptosis resistance and collagen synthesis in lung fibroblasts These results indicate that mir-21 mediates the inhibitory effect of ACE2/Ang[1,2,3,4,5,6,7] on AngII-induced activation of the NLRP3 inflammasome by targeting Spry in lung fibroblasts. A direct target of mir-21, augments extracellular signal-regulated kinase (ERK) activity in cardiac fibroblasts and hematopoietic stem cells (HSCs)9 It has not been determined whether mir-21 mediates pulmonary fibrosis via the ERK signaling pathway by targeting Spry. In a review of inflammasomes in liver diseases, Szabo & Csak cite data showing that IL-1Ra administration attenuates dimethylnitrosamine (DMN)-induced liver cirrhosis, and that www.nature.com/scientificreports/
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