Angiotensin-(1–7) Improves Liver Fibrosis by Regulating the NLRP3 Inflammasome <i>via</i> Redox Balance Modulation

Cai, Shuangming; Yang, Renqiang; Yang, Li; Ning, Zhu; Zhang, Lili; Zhou, Gao-su; Luo, Wei; Li, Da-Huan; Chen, Yan; Pan, Miao; Xu, Li

doi:10.1089/ars.2015.6498

Cited by 89 publications

(84 citation statements)

References 36 publications

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“…As for signal 2, we show for the first time that ROS generation and lysosome stability regulate Ang II activation of the NLRP3 inflammasome and effectuate the macrophage bacteria killing function. Similarly, a recent study demonstrated that the NLRP3 inflammasome is activated by Ang II via the Toll-like receptor 4 (TLR4)/MyD88/NF-κB pathway in hepatic fibrosis [37]. Nonetheless, our data imply that lysosome stability controls the NLRP3 inflammasome activation and functionality in response to Ang II in macrophages (Fig.…”

Section: Discussionsupporting

confidence: 71%

Cathepsin B-Mediated NLRP3 Inflammasome Formation and Activation in Angiotensin II -Induced Hypertensive Mice: Role of Macrophage Digestion Dysfunction

Lian

Lai

et al. 2018

Cell Physiol Biochem

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Background/Aims: Angiotensin II (Ang II) is an octapeptide hormone that plays a significant role in mediating hypertension. Although hypertension is considered a chronic inflammatory disease, the molecular basis of the sterile inflammatory response involved in hypertension remains unclear. Methods: We investigated the role of macrophage NLRP3 inflammasomes in engulfing and digesting microbes, a key macrophage function, and in early onset of hypertension-associated macrophage injury using biochemical analyses, gene silencing, molecular biotechnology, immunofluorescence, and microbiology. Results: Ang II stimulation decreased nitric oxide (NO) release and macrophage digestion in cultured THP-1 cells and markedly increased NLRP3 inflammasome formation and activation. NO release and macrophage digestion were restored by NLRP3 inflammasome inhibition with isoliquiritigenin and gene silencing. This Ang II-induced upregulation of NLRP3 inflammasomes in macrophages was attributed to lysosomal damage and release of cathepsin B. Mechanistically, losartan, a nonpeptide Ang II receptor antagonist, decreased Ang II-induced NLRP3 inflammasome activation, lysosomal membrane permeability, lysosomal cathepsin B release, and macrophage digestion dysfunction. Similarly, Ang II-induced macrophage microbe digestion and NO production, which were blocked by ATI gene silencing. In addition, in vivo experiments showed that the bacteria scavenging function was clearly decreased in macrophages from Ang II-induced hypertensive mice. Conclusion: Angiotensin II enhances lysosomal membrane permeabilization and the consequent release of lysosomal cathepsin B, resulting in activation of the macrophage NLRP3 inflammasome. This may contribute to NO mediation of dysfunction in digesting microbes.

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Section: Discussionsupporting

confidence: 71%

Cathepsin B-Mediated NLRP3 Inflammasome Formation and Activation in Angiotensin II -Induced Hypertensive Mice: Role of Macrophage Digestion Dysfunction

Lian

Lai

et al. 2018

Cell Physiol Biochem

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“…Our previous study (4) further confirmed that Ang II enhanced NOX4-derived ROS production in HSCs, leading to NLRP3 inflammasome activation and resultant collagen synthesis.…”

Section: Introductionsupporting

confidence: 67%

“…Ang-(1–7) protected against BDL- and AngII-induced liver fibrosis and inhibited expression of mir-21 . The principal findings obtained include the following: (1) mir-21 is positively correlated with liver fibrosis and oxidation; (2) both ERK/NF-κB and Smad3/NOX/ROS pathways mediate AngII-induced overexpression of mir-21 ; (3) mir-21 activates the ERK/NF-κB and Smad2/3/NOX4/ROS pathways in HSCs via targeting Spry1, Smad7 for degradation, respectively; (4) AngII activated NLRP3 inflammasome/IL-1β axis and thus promoted HSC activation via the mir-21 /Spry1/ERK/NF-κB and mir-21 /Smad7/Smad2/3/NOX4 pathway, respectively; and (5) Ang-(1–7) protected against BDL- or AngII-induced liver fibrosis and inhibited mir-21 expression.…”

Section: Discussionmentioning

confidence: 99%

“…As a vasoconstrictive peptide, AngII triggers hypertension by activation and infiltration of certain subsets of immune cells (11, 16, 40). In addition, being a pro-oxidative peptide, AngII triggers formation of NOX4-derived ROS (4, 25) and mitochondrial reactive oxygen species (mito-ROS) (6, 8, 15), the mito-ROS lead to white blood cell activation and inflammation (17). Interestingly, there exists interaction and cross-activation between AngII-induced mito-ROS and NADPH oxidase-dependent ROS (6, 8, 15).…”

Section: Introductionmentioning

confidence: 99%

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

Ning

Luo

Wang

et al. 2017

Antioxidants & Redox Signaling

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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.

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“…This study demonstrated that Ang-(1-7)/Mas axis prevented the rise of ROS levels induced by TGF-β1 in C 2 C 12 myotubes. These results concur with previous evidence indicating that Ang-(1-7) via the Mas receptor decreases oxidative stress in different cell types, such as adipocytes [49], cerebral endothelial cells [50], and, interestingly, in pathologies associated with skeletal muscle atrophy such as diabetes [51], cardiac failure [52], and hepatic damage [53]. Additionally, previously published results by us shows that Ang-(1-7)/Mas receptor prevents ROS induction by Ang-II in skeletal muscle cells [54].…”

Section: Discussionsupporting

confidence: 92%

Angiotensin-(1-7) Prevents Skeletal Muscle Atrophy Induced by Transforming Growth Factor Type Beta (TGF-β) via Mas Receptor Activation

Ábrigo

Simón

Cabrera

et al. 2016

Cell Physiol Biochem

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Background: Transforming growth factor type beta 1 (TGF-β1) produces skeletal muscle atrophy. Angiotensin-(1-7) (Ang-(1-7)), through the Mas receptor, prevents the skeletal muscle atrophy induced by sepsis, immobilization, or angiotensin II (Ang-II). However, the effect of Ang-(1-7) on muscle wasting induced by TGF-β1 is unknown. Aim: To evaluate whether Ang-(1-7)/Mas receptor axis could prevent the skeletal muscle atrophy induced by TGF-β1. Methods: This study assessed the atrophic effect of TGF-β1 in C₂C₁₂ myotubes and mice in absence or presence of Ang-(1-7), and the receptor participation using A779, an antagonist of the Mas receptor. The levels of myosin heavy chain (MHC), polyubiquitination, and MuRF-1 were detected by western blot. Myotube diameter was also evaluated. In vivo analysis included the muscle strength, fibre diameter, MHC and MuRF-1 levels by western blot, and ROS levels by DCF probe detection. Results: The results showed that Ang-(1-7) prevented the increase in MuRF-1 and polyubiquitined protein levels, the decrease of MHC levels, the myotubes/fibre diameter diminution, and the increased production of reactive oxygen species (ROS) induced by TGF-β1. Utilizing A779 inhibited the anti-atrophic effect of Ang-(1-7). Conclusion: The preventive effect of Ang-(1-7) on skeletal muscle atrophy induced by TGF-β1 is produced through inhibition of ROS production and proteasomal degradation of MHC.

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Angiotensin-(1–7) Improves Liver Fibrosis by Regulating the NLRP3 Inflammasome via Redox Balance Modulation

Abstract: 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.

Cited by 89 publications

References 36 publications

Cathepsin B-Mediated NLRP3 Inflammasome Formation and Activation in Angiotensin II -Induced Hypertensive Mice: Role of Macrophage Digestion Dysfunction

Cathepsin B-Mediated NLRP3 Inflammasome Formation and Activation in Angiotensin II -Induced Hypertensive Mice: Role of Macrophage Digestion Dysfunction

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

Angiotensin-(1-7) Prevents Skeletal Muscle Atrophy Induced by Transforming Growth Factor Type Beta (TGF-β) via Mas Receptor Activation

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