Angiotensin-Converting Enzyme 2/Angiotensin-(1-7)/Mas Axis Protects against Lung Fibrosis by Inhibiting the MAPK/NF-κB Pathway

Abstract

Accumulating evidence has demonstrated that up-regulation of the angiotensin (Ang)-converting enzyme (ACE)/AngII/AngII type 1 receptor (AT1R) axis aggravates pulmonary fibrosis. The recently discovered ACE2/Ang-(1-7)/Mas axis, which counteracts the activity of the ACE/AngII/AT1R axis, has been shown to protect against pulmonary fibrosis. However, the mechanisms by which ACE2 and Ang-(1-7) attenuate pulmonary fibrosis remain unclear. We hypothesized that up-regulation of the ACE2/Ang-(1-7)/Mas axis protects against bleomycin (BLM)-induced pulmonary fibrosis by inhibiting the mitogen-activated protein kinase (MAPK)/NF-κB pathway. In vivo, Ang-(1-7) was continuously infused into Wistar rats that had received BLM or AngII. In vitro, human fetal lung-1 cells were pretreated with compounds that block the activities of AT1R, Mas (A-779), and MAPKs before exposure to AngII or Ang-(1-7). The human fetal lung-1 cells were infected with lentivirus-mediated ACE2 before exposure to AngII. In vivo, Ang-(1-7) prevented BLM-induced lung fibrosis and AngII-induced lung inflammation by inhibiting the MAPK phosphorylation and NF-κB signaling cascades. However, exogenous Ang-(1-7) alone clearly promoted lung inflammation. In vitro, Ang-(1-7) and lentivirus-mediated ACE2 inhibited the AngII-induced MAPK/NF-κB pathway, thereby attenuating inflammation and α-collagen I production, which could be reversed by the Mas inhibitor, A-779. Ang-(1-7) inhibited AngII-induced lung fibroblast apoptotic resistance via inhibition of the MAPK/NF-κB pathway and activation of the BCL-2-associated X protein/caspase-dependent mitochondrial apoptotic pathway. Ang-(1-7) alone markedly stimulated extracellular signal-regulated protein kinase 1/2 phosphorylation and the NF-κB cascade. Up-regulation of the ACE2/Ang-(1-7)/Mas axis protected against pulmonary fibrosis by inhibiting the MAPK/NF-κB pathway. However, close attention should be paid to the proinflammatory effects of Ang-(1-7).

The Antimalarial Chloroquine Suppresses LPS-Induced NLRP3 Inflammasome Activation and Confers Protection against Murine Endotoxic Shock

“…We observed that CQ attenuated LPS-induced p65 phosphorylation (serine 536) and suppressed nucleus translocation of NF- κ B p65, which further demonstrated inhibition of the NF- κ B signaling pathway. The MAPK pathway also participates in the full activation of NF- κ B pathway as well as upregulation of IL-1 β and IL-18 [30, 31]. Our results also demonstrated that CQ inhibited phosphorylation of ERK1/2, p38, and JNK induced by LPS.…”

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

“…The absence of the antidiuretic action of Ang-(1-7) in Mas-KO mice is in agreement with the antidiuretic effect of Ang-(1-7) in water-loaded rats (Santos and Baracho, 1992). Diverging from many reports describing Mas-mediated anti-inflammatory effects in different tissues (Al-Maghrebi et al, 2009;da Silveira et al, 2010;El-Hashim et al, 2012;Giani et al, 2012;Jiang et al, 2012;Santos et al, 2012;Souza and Costa-Neto, 2012;Sukumaran et al, 2012;Chen et al, 2013;Feltenberger et al, 2013;Moore et al, 2013;Regenhardt et al, 2013;Wagenaar et al, 2013;Wang et al, 2013c;Acuna et al, 2014;Meng et al, 2014), in the kidney, a proinflammatory role for Ang-(1-7) and Mas was reported by using a model of unilateral ureteral obstruction in mice (Esteban et al, 2009). In contrast, anti-inflammatory and beneficial effects of Ang-(1-7) were observed in other models of kidney injury (Singh et al, 2010b;Moon et al, 2011;Bernardi et al, 2012;Giani et al, 2012;Harris, 2012;Chou et al, 2013;Santos et al, 2013b;Zhang et al, 2014).…”

Endothelial Cell Regulation of Pulmonary Vascular Tone, Inflammation, and Coagulation

“…This effect was mediated by inhibition of JNK (231). Finally, Ang-(1-7) has also been shown to inhibit signalling through MAPK and NF-κB (145).…”

“…The discovery of the Ang-(1-7)-Mas axis generated a great deal of interest since the effects of this pathway were thought to antagonize AngII (62,145). In a model of bleomycininduced pulmonary fibrosis, rats were protected from fibrosis by infusion of Ang-(1-7) (145).…”