Changhui Lang
Bo Huang
Yan Chen1,2- 1Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
- 2Guizhou Children's Hospital, Zunyi, Guizhou, China
Pulmonary fibrosis (PF), a progressive and fatal disease, is characterized by fibroblast proliferation, excessive extracellular matrix deposition, and collagen synthesis. These pathological changes lead to impaired lung structure and function, ultimately resulting in respiratory failure. Emerging basic and clinical evidence highlight the renin–angiotensin system (RAS) as a critical contributor to PF onset and progression. Angiotensin (Ang) II, a key RAS component, mediates various biological effects through its receptors, Ang II receptor type 1 (AT1R) and Ang II receptor type 2 (AT2R). Ang II promotes vasoconstriction, inflammation, and fibrosis via AT1R, while it shows contrasting effects through AT2R. Angiotensin-converting enzyme 2 (ACE2) plays a significant role in RAS by converting Ang II into Ang (1–7), which in turn interacts with Mas receptor and Mas-associated G-protein-coupled receptor D to exert anti-inflammatory, anti-apoptotic, and anti-fibrotic effects. The RAS also influences autophagy, oxidative stress, and inflammation in the progression of PF. This review provides an updated overview of the roles of the classical and non-classical RAS pathways in PF.
1 Introduction
Pulmonary fibrosis (PF) is a rapidly progressive and fatal condition with high morbidity and mortality, often secondary to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). PF is characterized by repetitive epithelial injury, epithelial–mesenchymal transition (EMT), endothelial–mesenchymal transition, cell senescence, fibroblast activation, proliferation, extensive extracellular matrix (ECM) accumulation, lung architectural distortion, and pulmonary dysfunction. Its etiology remains unknown. PF leads to a gradual decline in lung function, resulting in end-stage respiratory failure (1, 2). In the context of the complexity of PF pathogenesis, current treatments, such as pirfenidone and nintedanib, primarily aim to slow fibrosis progression. However, an optimal therapeutic strategy for PF has yet to be established (3–5). Therefore, identifying novel therapeutic targets for PF remains critically important.
The renin–angiotensin system (RAS) is widely recognized for its essential role in regulating blood pressure, electrolyte balance, and blood volume. Components of RAS are identified in various organs, including the heart, blood vessels, lungs, and kidneys (6). It comprises two subsystems: the classical RAS and the non-classical or alternative RAS (7). The classical RAS primarily includes angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and the Ang II receptor type 1 (AT1R). In this system, renin converts angiotensinogen (AGT) into Ang I, a substrate for the ubiquitously expressed ACE, particularly in lung tissue. ACE further processes Ang I into Ang II, the key effector of the classical RAS, which exerts various physiological effects by binding to specific receptors, AT1R and AT2R (8). Ang II promotes vasoconstriction, pro-inflammatory, pro-apoptotic, and pro-fibrotic activities, as well as sodium balance regulation, primarily through AT1R. However, Ang II has been shown to elicit opposing effects when interacting with AT2R (9). Ang II is degraded by ACE2, a key regulator that counteracts the effects of the classical RAS (10). Ang II can also be hydrolyzed by aminopeptidase A (APA) into Ang III and then converted to Ang IV by aminopeptidase N (APN) (11). Ang II activates a range of intracellular protein kinases, including receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR), as well as non-receptor tyrosine kinases such as Src, which is upregulated in PF and accelerates the release of transforming growth factor-β1 (TGF-β1). Moreover, Ang II stimulates serine/threonine kinases such as mitogen-activated protein kinase (MAPK), Akt/protein kinase B, and various protein kinase C isoforms (12).
The alternative RAS, comprising ACE2, Ang (1–7), and the Mas receptor (MasR), plays vasodilatory, anti-inflammatory, and anti-fibrotic roles in respiratory diseases such as ARDS (13). In the non-classical RAS, ACE2 cleaves Ang I to produce the Ang (1–9) peptide, which counteracts the ACE arm. Ang (1–9) can later be converted into Ang (1–7) by ACE or neprilysin (NEP) (14). NEP (15), a membrane metalloendopeptidase (MME), directly processes Ang I into Ang (1–7), improving its protective effects, particularly in the lung, especially in the presence of ACE inhibitors (16). NEP also hydrolyzes endothelin-1 (ET-1), a known bronchoconstrictor and vasoconstrictor in the airways, mitigating inflammatory responses and preventing the fibrotic cascade in the lung (17). The increase in plasma ET-1 levels is linked to Ang II release. ET-1 contributes to pulmonary vascular remodeling, potentially leading to pulmonary arterial hypertension (PAH) secondary to bleomycin (BLM)-induced PF (14, 18). ET-1 also stimulates the release of TGF-β1 following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This process drives endothelial dysfunction that can result in vascular constriction and increased vascular permeability (19, 20). Ang (1–7), which is hydrolyzed by ACE into Ang (1–5), was initially considered biologically inactive (14). However, recent evidence suggests that Ang (1–5) promotes NO release by activation of eNOS via interaction with the AT2R (21).
The non-classical RAS also facilitates the conversion of Ang II into the vasodilator Ang (1–7) via ACE2, thereby counteracting the effects of Ang II. Furthermore, ACE2 degrades Ang A (an aspartate-to-alanine homolog of Ang II) into another vasodilator, alamandine (ALA) (22). ALA interacts with the Mas-related G-protein-coupled receptor D (MrgD), playing a protective role in opposing the classical RAS and mitigating fibrosis (23) (Figure 1).
Figure 1. Schematic diagram of the local renin–angiotensin system and ACE2/Ang (1–7)/Mas axis in pulmonary fibrosis. AGT, angiotensinogen; Ang I, angiotensin I; Ang II, angiotensin II; Ang III, angiotensin III; Ang IV, angiotensin IV; ACE2, angiotensin-converting enzyme2; NEP, neprilysin/neutral endopeptidase; ACE, angiotensin-converting enzyme; ET-1, endothelin-1; AT2R, angiotensin II type 2 receptor; AT1R, angiotensin II type 1 receptor; APA, aminopeptidase A; APN, aminopeptidase N; Ang A, angiotensin A; TGF-β1, transforming growth factor-β1; EMT, epithelial–mesenchymal transition; NO, nitric oxide; EndoMT, endothelial–mesenchymal transition; MasR, Mas receptor; MrgD, Mas-related G-protein-coupled receptor D.
Under normal physiological conditions, the classical and non-classical RAS maintain a delicate balance. Emerging evidence indicates that the dysregulation of the RAS is associated with the progression of various diseases, particularly cardiovascular diseases and PAH (24), chronic obstructive pulmonary disease (COPD) (8), and ALI (25). The RAS also plays a critical role in regulating various cellular processes, including inflammation, proliferation, and apoptosis. It is also implicated in endothelial dysfunction and vascular remodeling in animal models of PAH (26, 27). ACE2, a key component of the non-classical RAS, is closely associated with PAH. Reduced ACE2 activity is closely linked to the development of PAH, while its upregulation has been shown to improve pulmonary homeostasis, reduce oxidative stress, and suppress inflammatory mediators (28). The ACE2 activator diminazene aceturate (DIZE) alleviates monocrotaline-induced PAH and restores the imbalance caused by monocrotaline (29). Increasing evidence supports the link between dysregulated RAS and the development and progression of PF (30, 31). Previous studies have shown that local RAS activation contributes to PF development induced by hyperoxia in neonatal rats (32). Moreover, ACE inhibitors and non-selective Ang II receptor antagonists, such as saralasin, effectively block experimental lung fibrosis in animal models (9).
Further research is needed to fully understand the role of the classical RAS and the ACE2/Ang (1–7)/Mas network in PF. The ACE2/Ang (1–7)/Mas network may serve as a potential therapeutic target for PF. This review offers a comprehensive overview of the relationship between the classical RAS and the ACE2/Ang (1–7)/Mas network in PF.
2 The roles of the ACE/Ang II/AT1R pathway in PF
The ACE/Ang II/AT1R network is a key regulator in the development of PF (30, 31). Elevated renin levels have been observed in the lungs and fibroblasts of patients with PF, correlating with increased expression of TGF-β1. This cytokine is pivotal in driving fibrosis by promoting fibroblast activation and ECM deposition, resulting in tissue scarring and compromised organ function. Furthermore, renin suppresses the expression of matrix metalloproteinase-1 (MMP-1), an enzyme involved in ECM degradation. Knocking down renin results in a significant decrease in TGF-β1 levels (33).
Ang II is the primary effector in the classical RAS system. Ang II can stimulate the formation of fibrosis via AT1R in various tissues, including the heart, kidney, and lungs (34). Elevated levels of Ang II and AT1R have been observed in a PF rat model induced by BLM, and inhibiting Ang II alleviates structural damage to lung tissue (35). Treatment with AT1R antagonists has been shown to reduce the expression of alpha-smooth muscle actin (α-SMA) in PF induced by hyperoxia in neonatal rats (36). An increase in Ang II leads to the accumulation of collagen in the lungs (37). Furthermore, the rise in TGF-β1 and collagen deposition caused by Ang II was blocked by AT1R-selective antagonists such as L158809 or losartan (9). Following BLM exposure, the severity of lung fibrosis and the hydroxyproline levels were significantly reduced by the AT1R antagonist olmesartan medoxomil (38).
As previously mentioned, Ang II has antifibrotic effects when binding to AT2R (9). The AT2R agonist compound 21 prevented the development of lung fibrosis induced by BLM at day 0 or halted its progression at day 3 (39), suggesting that Ang II plays distinct roles depending on which receptor it binds to. Ang II plays a significant role in signaling pathways critical to fibrosis pathogenesis. The primary pathway mediated by BLM in PF is the activation of the small mothers against decapentaplegic homologs (Smad)/TGF-β signaling cascade (40). Elevated levels of collagen I, AT1R, TGF-β1, and phosphorylated Smad2/3 (p-Smad2/3) have been detected in lung fibroblasts stimulated with macrophage-derived exosomes following Ang II exposure (41). Lung fibroblasts isolated from patients with PF produce Ang II, AGT, and α-SMA, which colocalize within myofibroblast foci (42). Inhibition of Ang II signaling reduces myofibroblast differentiation and ECM deposition in silicotic fibrosis models (43). Furthermore, targeting both the Ang II/AT1R axis and the TGF-β/Smad signaling pathway alleviates BLM-induced lung fibrosis (40).
The expression of AT1R is also upregulated in lung tissues affected by silicotic fibrosis (43). Elevated ACE, Ang II, and AT1R levels have been linked to right ventricular hypertrophy and hypoxia-induced fibrosis (44). The increased AT1R and reduced MasR have been observed in patients with PF. AT1R expression is inversely correlated with pulmonary function (45). Furthermore, the co-expression of ACE and AT1R in alveolar epithelial cells was significantly elevated in PF following mechanical ventilation (46). AT1R antagonists, such as losartan, or genetic disruption of the AT1R gene, reduce hydroxyproline accumulation and caspase-3 activity both in vitro and in vivo, including in models of lung fibrosis (47).
AT1R antagonists, such as losartan, have been shown to significantly improve lung function in patients with PF over 1 year (48). However, these findings require validation through larger, controlled clinical studies. Inhibition of Ang II synthesis using ACE inhibitors, including captopril and enalapril, has also been reported to reduce hydroxyproline content and TGF-β1 levels in animal models of PF (9, 49). Clinically, treatment with ACE inhibitors (e.g., lisinopril and ramipril) or AT1R antagonists (e.g., valsartan and losartan) has been associated with decreased mortality risk and a slower rate of FVC decline in patients with PF, suggesting a potential disease-modifying effect in PF compared to patients not receiving ACE inhibitor or AT1R therapy (50). However, the interpretation of these findings is constrained by the retrospective nature of the exploratory analyses, which revealed associations between ACE inhibitor or Ang receptor blocker (ARB) use and clinical outcomes without establishing causality. These analyses are limited to patients receiving placebo treatment. Therefore, further prospective studies are needed to clarify the therapeutic impact of ACE inhibitors or AT1R antagonists, particularly in combination with approved antifibrotic agents, on clinical outcomes in PF.
Similarly, elevated ACE has been observed in the bronchoalveolar fluid of patients with fibrotic lung diseases (51). Single-nucleotide polymorphism insertion/deletion (I/D) mutations in the ACE gene can alter its function and activity. These mutations can lead to an increase in ACE activity, contributing to pulmonary inflammation and promoting lung fibrosis. Furthermore, an I/D polymorphism of ACE is linked to COPD (52, 53). A higher frequency of the D allele of the ACE gene is observed in patients with PF compared to healthy controls (54). The ACE I/D gene polymorphism is associated with the elevated risk of PF, particularly in the Chinese Han population (55). Moreover, ACE inhibitors such as captopril demonstrated efficacy in reducing collagen deposition in animal models exposed to irradiation (56–58). The above findings suggest that ACE plays a significant role in promoting the development of PF. These observations indicate that inhibiting Ang II or ACE may serve as a potential therapeutic approach for PF.
3 The significance of the ACE2/Ang (1–7)/Mas network in PF
ACE2, the primary receptor for SARS-CoV-2 entry into host cells (59, 60), is widely expressed in various organs, including the lungs (particularly on the surface of alveolar epithelial cells) (61), cardiovascular system, intestine (62), kidneys (63), central nervous system (64), and adipose tissue (65). It is also present in the testes and prostate tissues (66).
The risk of developing PF increases with decreased ACE2 levels in SARS-CoV-2-infected individuals, as ACE2 exerts anti-fibrotic effects post-infection (67, 68). However, reduced ACE2 levels may also offer protection against SARS-CoV-2 infection in susceptible populations, as ACE2 provides binding opportunities for the virus before infection (60, 62). These findings suggest that ACE2 plays distinct roles at different stages of infection.
ACE2 plays a significant role in the RAS by degrading Ang II to generate Ang (1–7) (68, 69). Ang (1–7) mitigates organ fibrosis, including that of the liver and lungs, by binding to MasR, which is encoded by the proto-oncogene Mas (70–72). It also inhibits tumor cell proliferation and modulates inflammation and angiogenesis in various types of tumors (73).
ACE2 and Ang (1–7) levels are significantly reduced following BLM administration (74). Both mRNA expression and activity of ACE2 are significantly decreased in experimental models of lung fibrosis and in patients with PF (75). Previous studies have shown that the alternative RAS pathway, including ACE2, mitigates inflammatory lung disease (76). The ACE2/Ang (1–7)/Mas pathway counteracts the adverse effects of the classical RAS, playing a critical role in regulating physiological and pathological functions in humans. ACE2 can suppress TGF-β1 signaling to inhibit EMT in alveolar epithelial cells induced by lipopolysaccharide (78). Activation of ACE2 using DIZE significantly increases E-cadherin levels while reducing α-SMA, collagen I, vimentin, hydroxyproline, and TGF-β1, therefore mitigating silica-induced lung fibrosis (77). It also modulates the TGF-β1/Smad2/Smad3 signaling pathway in type II alveolar epithelial cells, inhibiting collagen accumulation and TGF-β1 pathway activation (78). Exogenous ACE2 has been shown to attenuate BLM-induced fibrosis by preserving local ACE2 levels and preventing the increase of AGT (80). Overexpression of ACE2/Ang (1–7) reverses increased mRNA levels of TGF-β and other pro-inflammatory cytokines in BLM-treated rat models (79). Furthermore, ACE2 reduces apoptosis in alveolar type II epithelial cells induced by silica (80) while upregulation of ACE2 ameliorates fibrosis and EMT in these cells (81). Inhibiting ACE2, blocking the MasR, or knocking down the ACE2 gene worsens EMT, ECM accumulation, and lung dysfunction in silica-treated mice (83). ACE2-deficient mice show impaired exercise capacity, compromised lung function, and increased collagen deposition following BLM treatment compared to wild-type mice (82). These findings underscore that ACE2 alleviates EMT, ECM deposition, and TGF-β1 levels in vitro and in vivo, demonstrating its potential as a therapeutic target in lung fibrosis.
Furthermore, suppressing the ACE/Ang II/AT1R pathway using acetyl-seryl-asparyl-lysyl-proline, an anti-fibrotic peptide, reduces EMT and abnormal ECM deposition in silica-induced pulmonary interstitial fibrosis. This effect is mediated through the ACE2/Ang (1–7)/Mas pathway stimulation, thus protecting against fibrosis (83). Similarly, Ang (1–7) alleviates EMT induced by TGF-β1 (84). Exogenous Ang (1–7) enhances E-cadherin synthesis, reduces ECM formation induced by TGF-β1, and inhibits the phosphorylation of Smad2 and Smad3 (84). Overexpression of Ang (1–7) similarly decreases the deposition of excessive collagen, reduces mRNA levels of TGF-β, and suppresses the release of pro-inflammatory cytokines (79, 85, 86). Ang (1–7) alleviates EMT and decreases the production of AT1R and Ang II by inhibiting SRC kinase in early PF models induced by lipopolysaccharide. These effects are blocked by the MasR antagonist A779 (87). Collectively, these findings highlight the ACE2/Ang (1–7) pathway as a potent anti-fibrotic, anti-inflammatory, and anti-apoptotic pathway, making it a promising therapeutic target for PF.
4 Regulation of autophagy, oxidative stress, and inflammation in PF by classical RAS and ACE2/Ang (1–7)/Mas pathways
Increasing evidence suggests that oxidative stress and cytokine production are closely linked to the development of PF (88). Several studies have indicated that over-activated reactive oxygen species (ROS) contribute to the progression of PF (89, 90). Chronic inflammation in fibrosis persists, triggering excessive ROS production and TGF-β synthesis, which leads to fibroblast activation and ECM accumulation. Recent findings have highlighted that the Ang II and ACE2/Ang (1–7)/Mas network plays a significant role in mediating oxidative stress (91–93), autophagy (91, 94), and inflammation (95) during PF (Figure 2).
Figure 2. Role of RAS and the ACE2/Ang (1–7)/Mas focuses on ACE2 in pulmonary fibrosis. In pulmonary fibrosis, upregulated ACE/Ang II/AT1R axis and downregulated ACE2/Ang (1–7)/Mas axis exist, which can induce oxidative stress and inflammation. Over-expression of ACE2 can reduce oxidative stress and inflammation.
Ang II induces inflammation and oxidative stress through its interaction with AT1R (11, 47, 69). Ang II activates autophagy flux, intercellular ROS production, collagen synthesis, and NOD-like receptor family pyrin domain-containing 3 (NLRP3) expression. The profibrotic effect of BLM was reversed by autophagy inhibitors such as rapamycin and 3-MA, suggesting that inhibiting autophagy has an antifibrotic role in PF (91). The imbalance of autophagy caused by oxidative stress leads to increased ROS and apoptosis. ROS levels and oxidative stress markers are also upregulated in patients with PF, and high ROS levels are associated with poor prognosis. Combining pirfenidone and losartan (an AT1R antagonist) may provide stronger protection against PF than monotherapy by enhancing anti-inflammatory and antioxidant effects (96). A previous study suggested that ACE2 may regulate autophagy, as the autophagy inhibitor 3-MA mitigated the severity of ALI induced by lipopolysaccharide (LPS) (97). Furthermore, Ang (1–7) reduced NADPH oxidase 4 (NOX4) protein levels and inhibited autophagy, improving PF induced by smoking (98). Inhibiting autophagy also improved lung fibrosis in BLM-treated animals (91), which could be attributed to differences in the experimental models. However, contradictory reports exist regarding autophagy regulation by Ang II and the ACE2/Ang (1–7)/Mas network in PF. Overexpression of ACE2 in mice treated with BLM resulted in less collagen deposition and lower levels of NOX4, but higher LC3-II protein levels, indicating that ACE2 overexpression alleviated PF by enhancing autophagy (94). This suggests that autophagy may exert a dual role in PF. The seemingly contradictory reports regarding the role of ACE2-mediated autophagy in PF underscore the complexity of its dynamic regulatory networks and intricate microenvironmental influences during disease progression. To elucidate the precise mechanisms of the ACE2–autophagy axis across diverse etiologies and disease stages, future investigations should integrate cutting-edge single-cell sequencing technologies, dynamic pathological modeling, and comprehensive clinical cohort analyses.
The combination of AT1R antagonist losartan with pirfenidone reduced the release of inflammatory factors, such as interleukin-1β, tumor necrosis factor-α, TGF-β1, and platelet-derived growth factor, and reduced collagen formation. This suggests that the combined therapy has anti-inflammatory and anti-fibrotic effects in PF models treated with BLM (99). Overexpression of ACE2 in umbilical cord mesenchymal stem cells (ACE2-UCMSCs) has been shown to be more effective in reducing collagen deposition than either ACE2 or UCMSCs alone. In the ACE2-UCMSCs treatment group, fibrosis severity was attenuated, accompanied by a reduction in the release of inflammatory cytokines, including IL-1, IL-2, IL-6, and IL-10. These findings suggest that ACE2 and UCMSCs exert a synergistic effect on lung fibrosis caused by BLM (100). Bone marrow-derived mesenchymal stem cells (MSCs) overexpressing ACE2 improved the release of inflammatory mediators and pulmonary endothelial function in ALI induced by lipopolysaccharide (101). Exogenous Ang (1–7) and ACE2 together can reduce the synthesis and release of cytokines and chemokines, inhibit the migration of inflammatory cells to the lung, and improve pulmonary function (102, 103). Ang (1–7) significantly suppresses NADPH oxidase activation and inhibits nitric oxide synthase (NOS) release induced by both Ang II and IL-1β. Ang (1–7) can alleviate Ang II-driven vascular smooth muscle cell inflammation (104). Downstream cascades of Ang (1–7) help mitigate inflammation and fibrosis through the MasR (71, 95). Some studies have suggested that the anti-fibrotic effects of ALA (alpha-lipoic acid) occur by blocking oxidative stress and promoting autophagy. ALA also reduced the deposition of ECM components (such as collagen I and α-SMA) in fibroblasts challenged by Ang II, and its effects were suppressed by D-Pro7-Ang (1–7), a MrgD antagonist. These findings indicate that ALA alleviates PF by suppressing oxidative stress and activating autophagy (105, 106).
In human endothelial cells, Ang (1–7) enhances the release of nitric oxide (NO) and prostaglandins, promoting vasodilation by counteracting the vasoconstrictor effects of Ang II mediated by AT1R (107). The absence of NO exacerbates fibrotic changes in PF mice induced by BLM (108). NO also inhibits the release of connective tissue growth factor by blocking the Smad-dependent TGF-β signaling pathway. In cellular models, exogenous Ang (1–7) and ACE2 reduced inflammation and accumulation of collagen I induced by Ang II by inhibiting the MAPK/NF-κB pathway. These effects were reversed by the Mas inhibitor, A-779 (109). However, continuous infusion of Ang (1–7) paradoxically exacerbates lung inflammation. This paradox could be explained by the fact that, when the ACE/Ang II/AT1R pathway is stimulated by BLM or Ang II, exogenous Ang (1–7) suppresses the protein expressions of ACE/Ang II/AT1R while promoting the expression of ACE2, Ang (1–7), and Mas, activating Mas (an antagonist of AT1R) and inhibiting Ang II. However, Ang (1–7) may play a pro-inflammatory role when binding to AT1R in the absence of ACE/Ang II/AT1R stimulation (109). Furthermore, increased NO mediated by AT2R has been shown to reduce the production of pro-inflammatory cytokines and enhance the production of anti-inflammatory cytokines (110). Blocking MasR with A779 prevented the deposition of ECM. The Ang (1–7)/MasR pathway is also involved in the anti-inflammatory and anti-fibrotic effects of aerobic training in chronic asthma models (111). These findings suggest that the ACE2/Ang (1–7)/Mas pathway can reduce inflammation in lung fibrosis by increasing NO production and suppressing the expression of inflammatory factors.
5 Conclusion and perspectives
The over-activation of the ACE/Ang II/AT1R network results in an imbalance between the classic RAS and the ACE2/Ang (1–7)/Mas pathway, contributing to the initiation and progression of PF. ACE2, as an inverse modulator of the local RAS, facilitates the formation of Ang (1–7) from Ang II, thus regulating local Ang II levels and counteracting its harmful effects. Pharmacological agents that target the ACE/Ang II/AT1R network and upregulate the ACE2/Ang (1–7)/Mas pathway could offer promising therapeutic strategies for the treatment of PF in the future.
Author contributions
CL: Writing – original draft, Writing – review & editing. BH: Writing – review & editing, Supervision. YC: Supervision, Writing – review & editing. ZH: Funding acquisition, Writing – review & editing, Supervision.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This study was supported by the National Natural Science Foundation of China (32270848), the Guizhou Provincial Science and Technology Project (QKHCG[2024] ZD012), the Zunyi Municipal Science and Technology Project (ZSKRPT-2023-6 and ZSKHHZ-2024-218), and the Key Advantageous Discipline Construction Project of Guizhou Provincial Health Commission in 2023.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Gen AI was used in the creation of this manuscript.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
ACE, angiotensin-converting enzyme; AGT, angiotensinogen; Ang I, angiotensin I; Ang II, angiotensin II; ACE2, angiotensin-converting enzyme 2; ALA, alamandine; ALI, acute lung injury; ARDS, acute respiratory distress syndrome; α-SMA, α-smooth muscle actin; AT2R, angiotensin II type 2 receptor; AT1R, angiotensin II type 1 receptor; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; EndoMT, endothelial–mesenchymal transition; PF, pulmonary fibrosis; MAPK, mitogen-activated protein kinase; MasR, Mas receptor; MrgD, Mas-related G-protein-coupled receptor D; MSCs, mesenchymal stem cells; NOS, nitric oxide synthase; NO, nitric oxide; NADPH, nicotinamide adenine dinucleotide phosphate; PF, pulmonary fibrosis; PAH, pulmonary arterial hypertension; ROS, reactive oxygen species; RAS, renin angiotensin system; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Smad, small mothers against decapentaplegic homologs; TGF-β1, transforming growth factor-β1.
References
1. Ma H, Wu X, Li Y, Xia Y. Research progress in the molecular mechanisms, therapeutic targets, and drug development of idiopathic pulmonary fibrosis. Front Pharmacol. (2022) 13:963054. doi: 10.3389/fphar.2022.963054
2. Moss BJ, Ryter SW, Rosas IO. Pathogenic mechanisms underlying idiopathic pulmonary fibrosis. Annu Rev Pathol. (2022) 17:515–46. doi: 10.1146/annurev-pathol-042320-030240
3. Glass DS, Grossfeld D, Renna HA, Agarwala P, Spiegler P, DeLeon J, et al. Idiopathic pulmonary fibrosis: Current and future treatment. Clin Respir J. (2022) 16:84–96. doi: 10.1111/crj.13466
4. Inui N, Sakai S, Kitagawa M. Molecular pathogenesis of pulmonary fibrosis, with focus on pathways related to TGF-β and the ubiquitin-proteasome pathway. Int J Mol Sci. (2021) 22:6107. doi: 10.3390/ijms22116107
5. Spagnolo P, Kropski JA, Jones MG, Lee JS, Rossi G, Karampitsakos T, et al. Idiopathic pulmonary fibrosis: disease mechanisms and drug development. Pharmacol Ther. (2021) 222:107798. doi: 10.1016/j.pharmthera.2020.107798
6. Forrester SJ, Booz GW, Sigmund CD, Coffman TM, Kawai T, Rizzo V, et al. Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology. Physiol Rev. (2018) 98:1627–738. doi: 10.1152/physrev.00038.2017
7. Vargas Vargas RA, Varela Millán JM, Fajardo Bonilla E. Renin-angiotensin system: basic and clinical aspects-a general perspective. Endocrinol Diabetes Nutr. (2022) 69:52–62. doi: 10.1016/j.endien.2022.01.005
8. Shrikrishna D, Astin R, Kemp PR, Hopkinson NS. Renin-angiotensin system blockade: a novel therapeutic approach in chronic obstructive pulmonary disease. Clin Sci. (2012) 123:487–98. doi: 10.1042/CS20120081
9. Uhal BD, Kim JK, Li XP, Molina-Molina M. Angiotensin-TGF-beta 1 crosstalk in human idiopathic pulmonary fibrosis: autocrine mechanisms in myofibroblasts and macrophages. Curr Pharm Des. (2007) 13:1247–56. doi: 10.2174/138161207780618885
10. Imai Y, Kuba K, Penninger JM. The discovery of angiotensin-converting enzyme 2 and its role in ALI in mice. Exp Physiol. (2008) 93:543–8. doi: 10.1113/expphysiol.2007.040048
11. Gan PXL, Liao W, Linke KM, Mei D, Wu XD, Wong WSF. Targeting the reninangiotensin system for respiratory diseases. Adv Pharmacol. (2023) 98:111–44. doi: 10.1016/bs.apha.2023.02.002
12. Nakashima H, Suzuki H, Ohtsu H, Chao JY, Utsunomiya H, Frank GD, et al. Angiotensin II regulates vascular and endothelial dysfunction: recent topics of Angiotensin II type-1 receptor signaling in the vasculature. Curr Vasc Pharmacol. (2006) 4:67–78. doi: 10.2174/157016106775203126
13. Hrenak J, Simko F. Renin-angiotensin system: an important player in the pathogenesis of acute respiratory distress syndrome. Int J Mol Sci. (2020) 21:8038. doi: 10.3390/ijms21218038
14. Mohammed El Tabaa M, Mohammed El Tabaa M. Targeting Neprilysin (NEP) pathways: a potential new hope to defeat COVID-19 ghost. Biochem Pharmacol. (2020) 178:114057. doi: 10.1016/j.bcp.2020.114057
15. Bonvouloir N, Lemieux N, Crine P, Boileau G, DesGroseillers L. Molecular cloning, tissue distribution, and chromosomal localization of MMEL2, a gene coding for a novel human member of the neutral endopeptidase-2411 family DNA. Cell Biol. (2001) 20:493–8. doi: 10.1089/104454901316976127
16. Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. (2004) 383:45–51. doi: 10.1042/BJ20040634
17. Roksnoer LCW, Uijl E, de Vries R, Garrelds IM, Jan Danser AH. Neprilysin inhibition and endothelin-1 elevation: Focus on the kidney. Eur J Pharmacol. (2018) 824:128–32. doi: 10.1016/j.ejphar.2018.02.007
18. Hartopo AB, Arfian N, Nakayama K, Suzuki Y, Yagi K, Emoto N. Endothelial-derived endothelin-1 promotes pulmonary vascular remodeling in bleomycin-induced pulmonary fibrosis. Physiol Res. (2018) 67:S185–97. doi: 10.33549/physiolres.933812
19. Wermuth P J, Li ZD, Mendoza FA, Jimenez SA. Stimulation of transforming growth factor-β1-induced endothelial-to-mesenchymal transition and tissue fibrosis by endothelin-1 (ET-1): a novel profibrotic effect of ET-1. PLoS ONE. (2016) 11:e0161988. doi: 10.1371/journal.pone.0161988
20. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med. (2020) 8:807–15. doi: 10.1016/S2213-2600(20)30225-3
21. Souza-Silva IM, Peluso AA, Elsaafien K, Nazarova AL, Assersen KB, Rodrigues-Ribeiro L, et al. Angiotensin-(1-5) is a potent endogenous angiotensin AT 2 -receptor agonist. bioRxiv [Preprint]. (2024). doi: 10.1101/2024.04.05.588367
22. Jha S, Speth RC, Macheroux P. The possible role of a bacterial aspartate β-decarboxylase in the biosynthesis of alamandine. Med Hypotheses. (2020) 144:110038. doi: 10.1016/j.mehy.2020.110038
23. Fernandes RS, Netto MRT, Carvalho FB, Rigatto K. Alamandine: a promising treatment for fibrosis. Peptides. (2022) 157:170848. doi: 10.1016/j.peptides.2022.170848
24. Zhang F, Chen A, Pan Y, Wang X, Xu Y, Desai A, et al. Research progress on pulmonary arterial hypertension and the role of the angiotensin converting enzyme 2-angiotensin-(1-7)-mas axis in pulmonary arterial hypertension. Cardiovasc Drugs Ther. (2022) 36:363–70. doi: 10.1007/s10557-020-07114-6
25. Tan WSD, Liao W, Zhou S, Mei D, Wong WF. Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases. Curr Opin Pharmacol. (2018) 40:9–17. doi: 10.1016/j.coph.2017.12.002
26. Maron BA, Leopold JA. The role of the renin-angiotensin-aldosterone system in the pathobiology of pulmonary arterial hypertension (2013 grover conference series). Pulm Circ. (2014) 4:200–10. doi: 10.1086/675984
27. Li G, Liu Y, Zhu Y, Liu A, Xu Y, Li X, et al. ACE2 activation confers endothelial protection and attenuates neointimal lesions in prevention of severe pulmonary arterial hypertension in rats. Lung. (2013) 191:327–36. doi: 10.1007/s00408-013-9470-8
28. Hemnes AR, Rathinasabapathy A, Austin EA, Brittain EL, Carrier EJ, Chen X, et al. A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. Eur Respir J. (2018) 51:1702638. doi: 10.1183/13993003.02638-2017
29. Rigatto K, Casali KR, Shenoy V, Katovich MJ, Raizada MK. Diminazene aceturate improves autonomic modulation in pulmonary hypertension. Eur J Pharmacol. (2013) 713:89–93. doi: 10.1016/j.ejphar.2013.04.017
30. Delpino MV, Quarleri J. SARS-CoV-2 pathogenesis: imbalance in the renin-angiotensin system favors lung fibrosis. Front Cell Infect Microbiol. (2020) 10:340. doi: 10.3389/fcimb.2020.00340
31. Wang J, Chen L, Chen B, Meliton A, Liu SQ, Shi Y, et al. Chronic activation of the renin-angiotensin system induces lung fibrosis. Sci Rep. (2015) 5:15561. doi: 10.1038/srep15561
32. Jiang JS, Lang YD, Chou HC, Shih CM, Wu MY, Chen CM, et al. Activation of the renin-angiotensin system in hyperoxia-induced lung fibrosis in neonatal rats. Neonatology. (2012) 101:47–54. doi: 10.1159/000329451
33. Montes E, Ruiz V, Checa M, Melendez-Zajgla J, Montaño M, Ordoñez-Razo R, et al. Renin is an angiotensin-independent profibrotic mediator: role in pulmonary fibrosis. Eur Respir J. (2012) 39:141–8. doi: 10.1183/09031936.00130310
34. Murphy AM, Wong AL, Bezuhly M. Modulation of angiotensin II signaling in the prevention of fibrosis. Fibrogenesis Tissue Repair. (2015) 8:7. doi: 10.1186/s13069-015-0023-z
35. Li H, Wang YG, Chen TF, Gao YH, Song L, Yang YF, et al. Panax notoginseng saponin alleviates pulmonary fibrosis in rats by modulating the renin-angiotensin system. J Ethnopharmacol. (2024) 318:116979. doi: 10.1016/j.jep.2023.116979
36. Chou HC, Lang YD, Wang LF, Wu TY, Hsieh YF, Chen CM. Angiotensin II type 1 receptor antagonist attenuates lung fibrosis in hyperoxia-exposed newborn rats. J Pharmacol Exp Ther. (2012) 340:169–75. doi: 10.1124/jpet.111.186288
37. García-Martín A, Navarrete C, Garrido-Rodríguez M, Prados ME, Caprioglio D, Appendino G, et al. EHP-101 alleviates angiotensin II-induced fibrosis and inflammation in mice. Biomed Pharmacother. (2021) 142:112007. doi: 10.1016/j.biopha.2021.112007
38. Waseda Y, Yasui M, Nishizawa Y, Inuzuka K, Takato H, Ichikawa Y, et al. Angiotensin II type 2 receptor antagonist reduces bleomycin-induced pulmonary fibrosis in mice. Respir Res. (2008) 9:43. doi: 10.1186/1465-9921-9-43
39. Rathinasabapathy A, Horowitz A, Horton K, Kumar A, Gladson S, Unger T, et al. The selective angiotensin II type 2 receptor agonist, compound 21, attenuates the progression of lung fibrosis and pulmonary hypertension in an experimental model of bleomycin-induced lung injury. Front Physiol. (2018) 9:180. doi: 10.3389/fphys.2018.00180
40. Yu Q, Zhu D, Zou Y, Wang K, Rao PL, Shen YH. Catalpol attenuates pulmonary fibrosis by inhibiting ang II/AT1 and TGF-β/Smad-mediated epithelial mesenchymal transition. Front Med. (2022) 9:878601. doi: 10.3389/fmed.2022.878601
41. Sun NN, Zhang Y, Huang WH, Zheng BJ, Jin SY, Li X, et al. Macrophage exosomes transfer angiotensin II type 1 receptor to lung fibroblasts mediating bleomycin-induced pulmonary fibrosis. Chin Med J. (2021) 134:2175–85. doi: 10.1097/CM9.0000000000001605
42. Li X, Molina-Molina M, Abdul-Hafez A, Ramirez J, Serrano-Mollar A, Xaubet A, et al. Extravascular sources of lung angiotensin peptide synthesis in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. (2006) 291:887–95. doi: 10.1152/ajplung.00432.2005
43. Zhang Y, Yang F, Liu Y, Peng HB, Geng YC, Li SF, et al. Influence of the interaction between Ac SDKP and Ang II on the pathogenesis and development of silicotic fibrosis. Mol Med Rep. (2018) 17:7467–76. doi: 10.3892/mmr.2018.8824
44. Dang Z, Su S, Jin G, Nan X, Ma L, Li Z, et al. Tsantan sumtang attenuated chronic hypoxia-induced right ventricular structure remodeling and fibrosis by equilibrating local ACE-AngII-AT1R/ACE2-Ang1-7-Mas axis in rat. J Ethnopharmacol. (2020) 250:112470. doi: 10.1016/j.jep.2019.112470
45. Raupp D, Fernandes RS, Antunes KH, Perin FA, Rigatto K, et al. Impact of angiotensin II type 1 and G-protein-coupled Mas receptor expression on the pulmonary performance of patients with idiopathic pulmonary fibrosis. Peptides. (2020) 133:170384. doi: 10.1016/j.peptides.2020.170384
46. Feng J, Huang X, Xu Q, Tang R, Zhou Y, Qin S, et al. Pharmacological inhibition of the ACE/Ang-2/AT1 axis alleviates mechanical ventilation-induced pulmonary fibrosis. Int Immunopharmacol. (2024) 131:111855. doi: 10.1016/j.intimp.2024.111855
47. Li X, Rayford H, Uhal BD. Essential roles for angiotensin receptor AT1a in bleomycin-induced apoptosis and lung fibrosis in mice. Am J Pathol. (2003) 163:2523–30. doi: 10.1016/S0002-9440(10)63607-3
48. Couluris M, Kinder BW, Xu P, Gross-King M, Krischer J, Panos RJ. Treatment of idiopathic pulmonary fibrosis with losartan: a pilot project. Lung. (2012) 190:523–7. doi: 10.1007/s00408-012-9410-z
49. Molteni A, Wolfe LF, Ward WF, Ts'ao CH, Molteni LB, Veno P, et al. Effect of an angiotensin II receptor blocker and two angiotensin converting enzyme inhibitors on transforming growth factor-beta (TGF-beta) and alpha-actomyosin (alpha SMA), important mediators of radiation-induced pneumopathy and lung fibrosis. Curr Pharm Des. (2007) 13:1307–16. doi: 10.2174/138161207780618777
50. Kreuter M, Lederer DJ, Molina-Molina M, Noth I, Valenzuela C, Frankenstein L, et al. Association of angiotensin modulators with the course of idiopathic pulmonary fibrosis. Chest. (2019) 156:706–14. doi: 10.1016/j.chest.2019.04.015
51. Specks U, Martin WJ 2nd, Rohrbach MS. Bronchoalveolar lavage fluid angiotensin-converting enzyme in interstitial lung diseases. Am Rev Respir Dis. (1990) 141:117–23. doi: 10.1164/ajrccm/141.1.117
52. Wu X, Li W, Luo Z, Chen Y. Increased frequency of angiotensin-converting enzyme D allele in asian patients with chronic obstructive pulmonary disease: an updated meta-analysis. Clin Respir J. (2024) 18:e70002. doi: 10.1111/crj.70002
53. Xu G, Fan G, Sun Y, Yu L, Wu S, Niu W. Association of angiotensin-converting enzyme gene I/D polymorphism with chronic obstructive pulmonary disease: a meta-analysis. J Renin Angiotensin Aldosterone Syst. (2018) 19:1470320318770546. doi: 10.1177/1470320318770546
54. Morrison CD, Papp AC, Hejmanowski AQ, Addis VM, Prior TW. Increased D allele frequency of the angiotensin-converting enzyme gene in pulmonary fibrosis. Hum Pathol. (2001) 32:521–8. doi: 10.1053/hupa.2001.24321
55. Wu X, Li W, Huang G, Luo Z, Chen Y. Increased frequency of angiotensin converting enzyme D allele in Chinese Han patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Medicine. (2022) 101:e30942. doi: 10.1097/MD.0000000000030942
56. Kma L, Gao F, Fish BL, Moulder JE, Jacobs ER, Medhora M. Angiotensin converting enzyme inhibitors mitigate collagen synthesis induced by a single dose of radiation to the whole thorax. Radiat Res. (2012) 53:10–7. doi: 10.1269/jrr.11035
57. Medhora M, Gao F, Fish BL, Jacobs ER, Moulder JE, Szabo A. Dose-modifying factor for captopril for mitigation of radiation injury to normal lung. J Radiat Res. (2012) 53:633–40. doi: 10.1093/jrr/rrs004
58. Mahmood J, Jelveh S, Zaidi A, Doctrow SR, Medhora M, Hill RP. Targeting the renin-angiotensin system combined with an antioxidant is highly effective in mitigating radiation-induced lung damage. Int J Radiat Oncol Biol Phys. (2014) 89:722–8. doi: 10.1016/j.ijrobp.2014.03.048
59. Pagliaro P, Thairi C, Alloatti G, Penna C. Angiotensin-converting enzyme 2: a key enzyme in key organs. J Cardiovasc Med. (2022) 23:1–11. doi: 10.2459/JCM.0000000000001218
60. Scialo F, Daniele A, Amato F, Pastore L, Matera MG, Cazzola M, et al. ACE2: the major cell entry receptor for SARS-CoV-2. Lung. (2020) 198:867–77. doi: 10.1007/s00408-020-00408-4
61. Radzikowska U, Ding M, Tan G, Zhakparov D, Peng Y, Wawrzyniak P, et al. Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy. (2020)75:2829–45. doi: 10.1111/all.14429
62. Brevini T, Maes M, Webb GJ, John BV, Fuchs CD, Buescher G, et al. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature. (2023) 615:134–42. doi: 10.1038/s41586-022-05594-0
63. Hsu CN, Tain YL. Targeting the renin-angiotensin-aldosterone system to prevent hypertension and kidney disease of developmental origins. Int J Mol Sci. (2021) 22:2298. doi: 10.3390/ijms22052298
64. Feng P, Wu Z, Liu H, Shen Y, Yao X, Li X, et al. Electroacupuncture improved chronic cerebral hypoperfusion-induced anxiety-like behavior and memory impairments in spontaneously hypertensive rats by downregulating the ACE/Ang II/AT1R Axis and upregulating the ACE2/Ang-(1-7)/MasR axis. Neural Plast. (2020) 2020:9076042. doi: 10.1155/2020/9076042
65. Izquierdo AG, Carreira MC, Boughanem H, Moreno-Navarrete JM, Nicoletti CF, Oliver P, et al. Adipose tissue and blood leukocytes ACE2 DNA methylation in obesity and after weight loss. Eur J Clin Invest. (2022) 52:e13685. doi: 10.1111/eci.13685
66. Sharma I, Kumari P, Sharma A, Saha SC. SARS-CoV-2 and the reproductive system: known and the unknown!! Middle East Fertil Soc J. (2021) 26:1. doi: 10.1186/s43043-020-00046-z
67. Zhang L, Zhang Y, Qin X, Jiang X, Zhang J, Mao L, et al. Recombinant ACE2 protein protects against ALI induced by SARS-CoV-2 spike RBD protein. Crit Care. (2022) 26:171. doi: 10.1186/s13054-022-04034-9
68. Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, et al. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit Care. (2020) 24:422. doi: 10.1186/s13054-020-03120-0
69. Bourgonje AR, Abdulle AE, Timens W, Hillebrands JL, Navis GJ, Gordijn SJ, et al. Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol. (2020) 251:228–48. doi: 10.1002/path.5471
70. Cai SM, Yang RQ, Li Y, Ning ZW, Zhang LL, Zhou GS, et al. Angiotensin-(1-7) improves liver fibrosis by regulating the NLRP3 inflammasome via redox balance modulation. Antioxid Redox Signal. (2016) 24:795–812. doi: 10.1089/ars.2015.6498
71. Sheng M, Li Q, Huang W, Yu D, Pan H, Qian K, et al. Ang-(1-7)/Mas axis ameliorates bleomycin-induced pulmonary fibrosis in mice via restoration of Nox4-Nrf2 redox homeostasis. Eur J Pharmacol. (2024) 962:176233. doi: 10.1016/j.ejphar.2023.176233
72. Qaradakhi T, Gadanec LK, McSweeney KR, Tacey A, Apostolopoulos V, Levinger I, et al. The potential actions of angiotensin-converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases. Clin Exp Pharmacol Physiol. (2020) 47:751–8. doi: 10.1111/1440-1681.13251
73. de Paula Gonzaga ALAC, Palmeira VA, Ribeiro TFS, Costa LB, de Sá Rodrigues KE, Simões-E-Silva AC. ACE2/Angiotensin-(1-7)/Mas receptor axis in human cancer: potential role for pediatric tumors. Curr Drug Targets. (2020) 21:892–901. doi: 10.2174/1389450121666200210124217
74. Hao Y, Liu Y. Osthole alleviates bleomycin-induced pulmonary fibrosis via modulating angiotensin-converting enzyme 2/angiotensin-(1-7) axis and decreasing inflammation responses in rats. Biol Pharm Bull. (2016) 39:457–65. doi: 10.1248/bpb.b15-00358
75. Li X, Molina-Molina M, Abdul-Hafez A, Uhal V, Xaubet A, Uhal BD. Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis. Am J Physiol Lung Cell Mol Physiol. (2008) 295:L178–85. doi: 10.1152/ajplung.00009.2008
76. Sharma RK, Stevens BR, Obukhov AG, Grant MB, Oudit GY, Li Q, et al. ACE2 (Angiotensin-converting enzyme 2) in cardiopulmonary diseases: ramifications for the control of SARS-CoV-2. Hypertension. (2020) 76:651–61. doi: 10.1161/HYPERTENSIONAHA.120.15595
77. Li S, Li Y, Xu H, Wei Z, Yang Y, Jin F, et al. ACE2 attenuates epithelial-mesenchymal transition in MLE-12 cells induced by silica. Drug Des Devel Ther. (2020) 14:1547–59. doi: 10.2147/DDDT.S252351
78. Lin X, Lin W, Zhuang Y, Gao F. Angiotensin-converting enzyme 2 inhibits lipopolysaccharide-caused lung fibrosis via downregulating the transforming growth factor β-1/Smad2/Smad3 pathway. J Pharmacol Exp Ther. (2022) 381:236–46. doi: 10.1124/jpet.121.000907
79. Shenoy V, Ferreira AJ, Qi Y, Fraga-Silva RA, Díez-Freire C, Dooies A, et al. The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med. (2010) 182:1065–72. doi: 10.1164/rccm.200912-1840OC
80. Wang L, Wang Y, Yang T, Guo Y, Sun T. Angiotensin-converting enzyme 2 attenuates bleomycin-induced lung fibrosis in mice. Cell Physiol Biochem. (2015) 36:697–711. doi: 10.1159/000430131
81. Wang J, Xiang Y, Yang SX, Zhang HM, Li H, Zong QB, et al. MIR99AHG inhibits EMT in pulmonary fibrosis via the miR-136-5p/USP4/ACE2 axis. J Transl Med. (2022) 20:426. doi: 10.1186/s12967-022-03633-y
82. Rey-Parra GJ, Vadivel A, Coltan L, Hall A, Eaton F, Schuster M, et al. Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury. J Mol Med. (2012) 90:637–47. doi: 10.1007/s00109-012-0859-2
83. Li S, Li Y, Zhang Y, Li S, Zhang M, Jin F, et al. N-acetyl-seryl-asparyl-lysyl-proline regulates lung renin angiotensin system to inhibit epithelial-mesenchymal transition in silicotic mice. Toxicol Appl Pharmacol. (2020) 408:115255. doi: 10.1016/j.taap.2020.115255
84. Shao M, Wen ZB, Yang HH, Zhang CY, Xiong JB, Guan XX, et al. Exogenous angiotensin(1-7) directly inhibits epithelial-mesenchymal transformation induced by transforming growth factor-β1 in alveolar epithelial cells. Biomed Pharmacother. (2019) 117:109193. doi: 10.1016/j.biopha.2019.109193
85. Magalhaes GS, Villacampa A, Rodrigues-Machado MG, Campagnole-Santos MJ, Souza Santos RA, Sánchez-Ferrer CF, et al. Oral Angiotensin-(1-7) formulation after established elastase-induced emphysema suppresses inflammation and restores lung architecture. Front Pharmacol. (2025) 16:1540475. doi: 10.3389/fphar.2025.1540475
86. Chen Q, Yang Y, Huang Y, Pan C, Liu L, Qiu H. Angiotensin-(1-7) attenuates lung fibrosis by way of Mas receptor in acute lung injury. J Surg Res. (2013) 185:740–7. doi: 10.1016/j.jss.2013.06.052
87. Cao Y, Liu Y, Shang J, Yuan Z, Ping F, Yao S, et al. Ang-(1-7) treatment attenuates lipopolysaccharide-induced early pulmonary fibrosis. Lab Invest. (2019) 99:1770–83. doi: 10.1038/s41374-019-0289-7
88. Roksandic Milenkovic M, Klisic A, Ceriman V, Kotur Stevuljevic J, Savic Vujovic K, Mirkov D, et al. Oxidative stress and inflammation parameters-novel biomarkers for idiopathic pulmonary fibrosis. Eur Rev Med Pharmacol Sci. (2022) 26:927–34. doi: 10.26355/eurrev_202202_28002
89. Ning W, Xu X, Zhou S, Wu X, Wu H, Zhang Y, et al. Effect of high glucose supplementation on pulmonary fibrosis involving reactive oxygen species and TGF-β. Front Nutr. (2022) 9:998662. doi: 10.3389/fnut.2022.998662
90. Peng L, Wen L, Shi QF, Gao F, Huang B, Meng J, et al. Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-κB/NLRP3-mediated epithelial-mesenchymal transition and inflammation. Cell Death Dis. (2020) 11:978. doi: 10.1038/s41419-020-03178-2
91. Meng Y, Pan M, Zheng B, Chen Y, Li W, Yang Q, et al. Autophagy attenuates angiotensin II-induced pulmonary fibrosis by inhibiting redox imbalance-mediated NOD-like receptor family pyrin domain containing 3 inflammasome activation. Antioxid Redox Signal. (2019) 30:520–41. doi: 10.1089/ars.2017.7261
92. Meng Y, Li T, Zhou GS, Chen Y, Yu CH, Pang MX, et al. The angiotensin-converting enzyme 2/angiotensin (1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rho kinase pathway. Antioxid Redox Signal. (2015) 22:241–58. doi: 10.1089/ars.2013.5818
93. Li RJ, Wu CY, Ke HL, Wang XP, Zhang YW. Qing Fei Hua Xian decoction ameliorates bleomycin-induced pulmonary fibrosis by suppressing oxidative stress through balancing ACE-Ang II-AT1R/ACE2-Ang-(1-7)-Mas axis. Iran J Basic Med Sci. (2023) 26:107–13. doi: 10.22038/IJBMS.2022.67042.14700
94. Yang QJ, Zheng BB, Sun NN, Pan MX, Zheng ZM, Meng Y. Mechanism of angiotensin-converting enzyme 2 overexpression improving collagen synthesis in lung. Zhonghua Yi Xue Za Zhi. (2017) 97:770–6. doi: 10.3760/cma.j.issn.0376-2491.2017.10.011
95. Simões e Silva AC, Silveira KD, Ferreira AJ, Teixeira MM. ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. Br J Pharmacol. (2013) 169:477–92. doi: 10.1111/bph.12159
96. Lv XX, Li K, Hu Z. Autophagy and pulmonary fibrosis. Adv Exp Med Biol. (2020) 1207:569–79. doi: 10.1007/978-981-15-4272-5_40
97. Zhang X, Zheng J, Yan Y, Ruan Z, Su Y, Wang J, et al. Angiotensin-converting enzyme 2 regulates autophagy in acute lung injury through AMPK/mTOR signaling. Arch Biochem Biophys. (2019) 672:108061. doi: 10.1016/j.abb.2019.07.026
98. Pan M, Zheng Z, Chen Y, Sun N, Zheng B, Yang Q, et al. Angiotensin-(1-7) attenuated cigarette smoking-related pulmonary fibrosis via improving the impaired autophagy caused by nicotinamide adenine dinucleotide phosphate reduced oxidase 4-dependent reactive oxygen species. Am J Respir Cell Mol Biol. (2018) 59:306–19. doi: 10.1165/rcmb.2017-0284OC
99. Amirkhosravi A, Mirtajaddini Goki M, Heidari MR, Karami-Mohajeri S, Iranpour M, Torshabi M, et al. Combination of losartan with pirfenidone: a protective anti-fibrotic against pulmonary fibrosis induced by bleomycin in rats. Sci Rep. (2024) 14:8729. doi: 10.1038/s41598-024-59395-8
100. Min F, Gao F, Li Q, Liu Z. Therapeutic effect of human umbilical cord mesenchymal stem cells modified by angiotensin-converting enzyme 2 gene on bleomycin-induced lung fibrosis injury. Mol Med Rep. (2015) 11:2387–96. doi: 10.3892/mmr.2014.3025
101. He H, Liu L, Chen Q, Liu A, Cai S, Yang Y, et al. Mesenchymal stem cells overexpressing angiotensin-converting enzyme 2 rescue lipopolysaccharide-induced lung injury. Cell Transplant. (2015) 24:1699–715. doi: 10.3727/096368914X685087
102. Magalhães GS, Rodrigues-Machado MG, Motta-Santos D, Silva AR, Caliari MV, Prata LO, et al. Angiotensin-(1-7) attenuates airway remodeling and hyperresponsiveness in a model of chronic allergic lung inflammation. Br J Pharmacol. (2015) 172:2330–42. doi: 10.1111/bph.13057
103. Rodrigues Prestes TR, Rocha NP, Teixeira AL, Simoes-E-Silva AC. The anti-inflammatory potential of ACE2/angiotensin-(1-7)/Mas receptor axis: evidence from basic and clinical research. Curr Drug Targets. (2017) 18:1301–13. doi: 10.2174/1389450117666160727142401
104. Villalobos LA, San Hipólito-Luengo Á, Ramos-González M, Cercas E, Vallejo S, Romero A, et al. The angiotensin-(1-7)/Mas axis counteracts angiotensin II-dependent and -independent pro-inflammatory signaling in human vascular smooth muscle cells. Front Pharmacol. (2016) 7:482. doi: 10.3389/fphar.2016.00482
105. Liu Q, Zheng B, Zhang Y, Huang W, Hong Q, Meng Y. Alamandine via MrgD receptor attenuates pulmonary fibrosis via NOX4 and autophagy pathway. Can J Physiol Pharmaco. (2021) 99:885–93. doi: 10.1139/cjpp-2020-0662
106. Fernandes RS, Dias HB, de Souza Jaques WA, Becker T, Rigatto K. Assessment of alamandine in pulmonary fibrosis and respiratory mechanics in rodents. Renin Angiotensin Aldosterone Syst. (2021) 2021:9975315. doi: 10.1155/2021/9975315
107. Sampaio WO, Souza dos Santos RA, Faria-Silva R, da Mata Machado LT, Schiffrin EL, Touyz RM. Angiotensin-(1-7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension. (2007) 49:185–92. doi: 10.1161/01.HYP.0000251865.35728.2f
108. Noguchi S, Yatera K, Wang KY, Oda K, Akata K, Yamasaki K, et al. Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice. Respir Res. (2014) 15:92. doi: 10.1186/s12931-014-0092-3
109. Meng Y, Yu CH, Li W, Li T, Luo W, Huang S, et al. Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-κB pathway. Am J Respir Cell Mol Biol. (2015) 50:723–36. doi: 10.1165/rcmb.2012-0451OC
110. Young ON, Bourke JE, Widdop RE. Catch your breath: the protective role of the angiotensin AT2 receptor for the treatment of idiopathic pulmonary fibrosis. Biochem Pharmacol. (2023) 217:115839. doi: 10.1016/j.bcp.2023.115839
111. Gregório JF, Magalhães GS, Rodrigues-Machado MG, Gonzaga KER, Motta-Santos D, Cassini-Vieira P, et al. Angiotensin-(1-7)/Mas receptor modulates anti-inflammatory effects of exercise training in a model of chronic allergic lung inflammation. Life Sci. (2021) 282:119792. doi: 10.1016/j.lfs.2021.119792
Keywords: pulmonary fibrosis, angiotensin-converting enzyme 2, angiotensin 1–7, angiotensin II, renin-angiotensin system
Citation: Lang C, Huang B, Chen Y and He Z (2025) The role of the classical renin–angiotensin system and angiotensin-converting enzyme 2/Ang(1–7)/Mas axis in pulmonary fibrosis. Front. Med. 12:1615991. doi: 10.3389/fmed.2025.1615991
Received: 22 April 2025; Accepted: 01 July 2025;
Published: 29 July 2025.
Edited by:
Jane Elizabeth Bourke, Monash University, AustraliaReviewed by:
Olivia Young, Monash University, AustraliaCopyright © 2025 Lang, Huang, Chen and He. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhixu He, aHp4QGdtYy5lZHUuY24=