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Brain renin‐angiotensin (Ang) system (RAS) is implicated in neuroinflammation, a major characteristic of aging process. Angiotensin (Ang) II, produced by angiotensin‐converting enzyme (ACE), activates immune system via angiotensin type 1 receptor (AT1), whereas Ang(1–7), generated by ACE2, binds with Mas receptor (MasR) to restrain excessive inflammatory response. Therefore, the present study aims to explore the relationship between RAS and neuroinflammation. We found that repeated lipopolysaccharide (LPS) treatment shifted the balance between ACE/Ang II/AT1 and ACE2/Ang(1–7)/MasR axis to the deleterious side and treatment with either MasR agonist, AVE0991 (AVE) or ACE2 activator, diminazene aceturate, exhibited strong neuroprotective actions. Mechanically, activation of ACE2/Ang(1–7)/MasR axis triggered the Forkhead box class O1 (FOXO1)‐autophagy pathway and induced superoxide dismutase (SOD) and catalase (CAT), the FOXO1‐targeted antioxidant enzymes. Meanwhile, knockdown of MasR or FOXO1 in BV2 cells, or using the selective FOXO1 inhibitor, AS1842856, in animals, suppressed FOXO1 translocation and compromised the autophagic process induced by MasR activation. We further used chloroquine (CQ) to block autophagy and showed that suppressing either FOXO1 or autophagy abrogated the anti‐inflammatory action of AVE. Likewise, Ang(1–7) also induced FOXO1 signaling and autophagic flux following LPS treatment in BV2 cells. Cotreatment with AS1842856 or CQ all led to autophagic inhibition and thereby abolished Ang(1–7)‐induced remission on NLRP3 inflammasome activation caused by LPS exposure, shifting the microglial polarization from M1 to M2 phenotype. Collectively, these results firstly illustrated the mechanism of ACE2/Ang(1–7)/MasR axis in neuroinflammation, strongly indicating the involvement of FOXO1‐mediated autophagy in the neuroimmune‐modulating effects triggered by MasR activation. The neuroimmune‐regulatory mechanism of ACE2/Ang(1–7)/MasR axis. ACE2 cleaves AngII into Ang(1–7), which than binds with MasR. The activation of MasR triggers FOXO1 translocation and induces autophagic process, thereby accelerating the clearance of NLRP3 inflammasome.

To explore the potential therapeutic effects of angiotensin(1–7) (Ang(1–7)), an endogenous ligand of the Mas receptor, on streptozotocin-induced diabetic nephropathy, male Wistar rats were randomly divided into two groups: a control group and a diabetic model group. After 12 weeks, the diabetic rats were divided into subgroups for 4-week treatments consisting of no-treatment group, small-, moderate-, and large-dose Ang(1–7) groups, a valsartan group, a large-dose Ang(1–7) plus valsartan group, and an A779 (antagonist of the Mas receptor) group, each with 15 rats. Ang(1–7) improved renal function, attenuated glomeruli sclerosis, oxidative stress, and cell proliferation, decreased the expression of collagen IV, TGF-β1, VEGF, NOX4, p47phox, PKCα, and PKCβ1, and the phosphorylation of Smad3. In the rat mesangial HBZY-1 cell line, Ang(1–7) decreased high-glucose-induced oxidative stress, the proliferation and expression of NOX4, p47phox, and TGF-β1, the phosphorylation of Smad3, collagen IV, and VEGF, and the membrane translocation of PKCα and PKCβ1. A779 blocked the effects of Ang(1–7) both in vivo and in vitro. The effects of large-dose Ang(1–7) alone and in combination with valsartan were superior to valsartan alone, but the combination had no significant synergistic effect compared with Ang(1–7) alone. Thus, Ang(1–7) ameliorated streptozotocin-induced diabetic renal injury. Large-dose treatment was superior to valsartan in reducing oxidative stress and inhibiting TGFβ1/Smad3- and VEGF-mediated pathways.

Early pulmonary fibrosis is the leading cause of poor prognosis in patients with acute respiratory distress syndrome (ARDS). However, whether the renin-angiotensin system (RAS) can serve as a therapeutic target is unknown. In this study, an animal model of early pulmonary fibrosis was established via the LPS three-hit regimen. Afterwards, the animals were treated with intraperitoneal injections of Ang-(1-7), AVE0991, or A779 once per day for 20 days. The plasma and BALF AngII levels of the animals were increased, while there were no significant changes in Ang-(1-7) levels in lung tissue after LPS treatment. Furthermore, the AT1R protein levels were significantly increased and the Mas levels were significantly decreased on days 14 and 21. Administration of Ang-(1-7) downregulated LPS-induced AT1R mRNA expression, which was upregulated by A779. The expression of Mas mRNA responded in the opposite direction relative to AT1R. Moreover, LPS caused decreased levels of Mas and E-cadherin and increased AT1R, Vimentin, and Src phosphorylation levels. Ang-(1-7) or AVE0991 blocked these effects but was counteracted by A779 treatment. Our findings suggested that AngII and AT1R levels exhibit opposite dynamic trends during LPS-induced early pulmonary fibrosis, as do Ang-(1-7) and Mas. Ang-(1-7) exerts protective effects against early pulmonary fibrosis, mainly by regulating the balance between AngII and AT1R and between Ang-(1-7) and Mas and by inhibiting Src kinase activation.

Angiotensin-(1-7) (Ang-(1-7)) can regulate vascular inflammation and remodeling, which are processes that have important roles in the pathophysiology of intracranial aneurysms. In this study, we assessed the effects of Ang-(1-7) in the development of intracranial aneurysm rupture using a mouse model of intracranial aneurysms in which aneurysmal rupture (i.e., aneurysmal subarachnoid hemorrhage) occurs spontaneously and causes neurologic symptoms. Treatment with Ang-(1-7) (0.5 mg/kg/day), Mas receptor antagonist (A779 0.5 mg/kg/day or 2.5 mg/kg/day), or angiotensin II type 2 receptor (AT2R) antagonist (PD 123319, 10 mg/kg/day) was started 6 days after aneurysm induction and continued for 2 weeks. Angiotensin-(1-7) significantly reduced the rupture rate of intracranial aneurysms without affecting the overall incidence of aneurysms. The protective effect of Ang-(1-7) was blocked by the AT2R antagonist, but not by the Mas receptor antagonist. In AT2R knockout mice, the protective effect of Ang-(1-7) was absent. While AT2R mRNA was abundantly expressed in the cerebral arteries and aneurysms, Mas receptor mRNA expression was very scarce in these tissues. Angiotensin-(1-7) reduced the expression of tumor necrosis factor-α and interleukin-1β in cerebral arteries. These findings indicate that Ang-(1-7) can protect against the development of aneurysmal rupture in an AT2R-dependent manner.

Angiotensin converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system (RAS), catalyzing the conversion of Angiotensin II to Angiotensin 1-7. Apelin is a second catalytic substrate for ACE2 and functions as an inotropic and cardioprotective peptide. While an antagonistic relationship between the RAS and apelin has been proposed, such functional interplay remains elusive. Here we found that ACE2 was downregulated in apelin-deficient mice. Pharmacological or genetic inhibition of angiotensin II type 1 receptor (AT1R) rescued the impaired contractility and hypertrophy of apelin mutant mice, which was accompanied by restored ACE2 levels. Importantly, treatment with angiotensin 1-7 rescued hypertrophy and heart dysfunctions of apelin-knockout mice. Moreover, apelin, via activation of its receptor, APJ, increased ACE2 promoter activity in vitro and upregulated ACE2 expression in failing hearts in vivo. Apelin treatment also increased cardiac contractility and ACE2 levels in AT1R-deficient mice. These data demonstrate that ACE2 couples the RAS to the apelin system, adding a conceptual framework for the apelin-ACE2-angiotensin 1-7 axis as a therapeutic target for cardiovascular diseases.

We have shown that angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)] increased arterial blood pressure (BP) via glutamate release when microinjected into the rostral ventrolateral medulla (RVLM) in normotensive rats (control). In the present study, we tested the hypothesis that Ang II and Ang-(1-7) in the RVLM are differentially activated in stress-induced hypertension (SIH) by comparing the effects of microinjection of Ang II, Ang-(1-7), and their receptor antagonists on BP and amino acid release in SIH and control rats. We found that Ang II had greater pressor effect, and more excitatory (glutamate) and less inhibitory (taurine and γ-aminobutyric acid) amino acid release in SIH than in control animals. Losartan, a selective AT₁ receptor (AT₁R) antagonist, decreased mean BP in SIH but not in control rats. PD123319, a selective AT₂ receptor (AT₂R) antagonist, increased mean BP in control but not in SIH rats. However, Ang-(1-7) and its selective Mas receptor antagonist Ang779 evoked similar effects on BP and amino acid release in both SIH and control rats. Furthermore, we found that in the RVLM, AT₁R, ACE protein expression (western blot) and ACE mRNA (real-time PCR) were significantly higher, whereas AT₂R protein, ACE2 mRNA and protein expression were significantly lower in SIH than in control rats. Mas receptor expression was similar in the two groups. The results support our hypothesis and demonstrate that upregulation of Ang II by AT₁R, not Ang-(1-7), system in the RVLM causes hypertension in SIH rats by increasing excitatory and suppressing inhibitory amino acid release.

Background Alterations in the renin–angiotensin system have been implicated in the pathophysiology of septic shock. In particular, angiotensin 1–7 (Ang-(1–7)), an anti-inflammatory heptapeptide, has been hypothesized to have beneficial effects. The aim of the present study was to test the effects of Ang-(1–7) infusion on the development and severity of septic shock. Methods This randomized, open-label, controlled study was performed in 14 anesthetized and mechanically ventilated sheep. Immediately after sepsis induction by bacterial peritonitis, animals received either Ang-(1–7) ( n  = 7) or placebo ( n  = 7) intravenously. Fluid resuscitation, antimicrobial therapy, and peritoneal lavage were initiated 4 h after sepsis induction. Norepinephrine administration was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg. Results There were no differences in baseline characteristics between groups. Septic shock was prevented in 6 of the 7 animals in the Ang-(1–7) group at the end of the 24-h period. Fluid balance and MAP were similar in the two groups; however, MAP was achieved with a mean norepinephrine dose of 0.4 μg/kg/min in the Ang-(1–7) group compared to 4.3 μg/kg/min in the control group. Heart rate and cardiac output index were lower in the Ang (1–7) than in the control group, as were plasma interleukin-6 levels, and creatinine levels. Platelet count and PaO 2 /FiO 2 ratio were higher in the Ang-(1–7) group. Mean arterial lactate at the end of the experiment was 1.6 mmol/L in the Ang-(1–7) group compared to 7.4 mmol/L in the control group. Conclusions In this experimental septic shock model, early Ang-(1–7) infusion prevented the development of septic shock, reduced norepinephrine requirements, limited interleukine-6 increase and prevented renal dysfunction.

Background . Acute kidney injury (AKI) often progresses to chronic kidney disease (CKD), presenting a significant clinical challenge. The renin-angiotensin system (RAS), particularly the protective arm involving Angiotensin-(1–7) (Ang-(1–7)), offers a potential therapeutic target to mitigate this progression. This study explores the effects of Ang-(1–7) in a murine model of ischemia-reperfusion (I/R) injury-induced AKI.  Methods.  Adult male Balb/c mice were subjected to bilateral renal I/R injury to induce AKI. Mice were then treated with various doses of Ang-(1–7). Key methods included enzyme-linked immunosorbent assay (ELISA) for serum biomarkers, immunohistochemistry for tissue-specific protein expression, and Western blotting for signaling pathway analysis. Key endpoints included serum levels of Angiotensin II (Ang II), Transforming Growth Factor-β1 (TGF-β1), Collagen I, and Superoxide Dismutase (SOD).  Results . Ang-(1–7) treatment significantly reduced serum Ang II and TGF-β1 levels and decreased renal Collagen I expression. Notably, a dose-dependent increase in SOD was observed, indicating enhanced antioxidant defense. Additionally, Ang-(1–7) administration led to a marked reduction in renal fibrosis markers and inflammatory cytokines, including TGF-β1 and Collagen I, particularly in the high-dose group. The treatment also modulated the expression of key proteins involved in the RAS pathway, such as increased Angiotensin-Converting Enzyme 2 (ACE2) and decreased Angiotensin II Receptor Type 1 (AT1R) expression.  Conclusion . This study highlights the novel therapeutic potential of Ang-(1–7) in preventing AKI progression to CKD by modulating the RAS towards a protective state. The findings provide a strong rationale for further clinical investigation of Ang-(1–7) or Mas receptor agonists as viable therapeutic strategies in kidney disease management.

Angiotensin-(1-7) [Ang-(1-7)] counteracts many actions of the renin-angiotensin-aldosterone system. Despite its renoprotective effects, extensive controversy exists regarding the role of Ang-(1-7) in obstructive nephropathy, which is characterized by renal tubulointerstitial fibrosis and apoptosis. To examine the effects of Ang-(1-7) in unilateral ureteral obstruction (UUO), male Sprague-Dawley rats were divided into three groups: control, UUO, and Ang-(1-7)-treated UUO rats. Ang-(1-7) was continuously infused (24 μg/[kg·h]) using osmotic pumps. We also treated NRK-52E cells in vitro with Ang II (1 μM) in the presence or absence of Ang-(1-7) (1 μM), Mas receptor antagonist A779 (1 μM), and Mas receptor siRNA (50 nM) to examine the effects of Ang-(1-7) treatment on Ang II-stimulated renal injury via Mas receptor. Angiotensin II (Ang II) and angiotensin type 1 receptor (AT1R) protein expression was higher in UUO kidneys than in controls. Ang-(1-7) treatment also decreased proapoptotic protein expression in UUO kidneys. Ang-(1-7) also significantly ameliorated TUNEL positive cells in UUO kidneys. Additionally, Ang-(1-7) reduced profibrotic protein expression and decreased the increased tumor growth factor (TGF)-β1/Smad signaling present in UUO kidneys. In NRK-52E cells, Ang II induced the expression of TGF-β1/Smad signaling effectors and proapoptotic and fibrotic proteins, as well as cell cycle arrest, which were attenuated by Ang-(1-7) pretreatment. However, treatment with A779 and Mas receptor siRNA enhanced Ang II-induced apoptosis and fibrosis. Moreover, Ang II increased tumor necrosis factor-α converting enzyme (TACE) and decreased angiotensin-converting enzyme 2 (ACE2) expression in NRK-52E cells, while pretreatment with Ang-(1-7) or A779 significantly inhibited or enhanced these effects, respectively. Ang-(1-7) prevents obstructive nephropathy by suppressing renal apoptosis and fibrosis, possibly by regulating TGF-β1/Smad signaling and cell cycle arrest via suppression of AT1R expression. In addition, Ang-(1-7) increased and decreased ACE2 and TACE expression, respectively, which could potentially mediate a positive feedback mechanism via the Mas receptor.

Purpose This randomized, double-blind, placebo-controlled Phase 2 study evaluated safety and efficacy of A(1–7) for reduction in Grade 3–4 thrombocytopenia in patients receiving myelosuppressive chemotherapy. Pharmacodynamic activity of A(1–7) in platelet production and retention of scheduled dose intensity were also determined. Methods Thirty-four patients with ovarian, Fallopian tube, or peritoneal carcinoma receiving gemcitabine and carboplatin or cisplatin were evaluated. Patients were randomized to receive study drug subcutaneously at 100 mcg/kg ( n  = 11), 300 mcg/kg ( n  = 13), or placebo ( n  = 10) following chemotherapy for up to six cycles. Hematologic variables were obtained throughout each treatment cycle. Results There were no drug-related safety issues. There were no instances of Grade 4 thrombocytopenia in patients who received 100 mcg/kg treatment compared to 6 % of chemotherapy cycles for patients receiving placebo ( p  = 0.07). The maximal percentage increase in platelet concentration from baseline was higher for patients who received 100 mcg/kg A(1–7) compared to placebo ( p  = 0.02). This increase was accompanied by a reduction in the nadir absolute neutrophil count ( p  = 0.04). Relative dose intensity for the combination chemotherapy was higher for patients who received 100 mcg/kg A(1–7) compared to placebo ( p  = 0.04). There were no differences in outcomes for patients receiving 300 mcg/kg dose compared to placebo. Conclusions A 100 mcg/kg dose of A(1–7) was shown to produce pharmacodynamic effects on peripheral blood platelet counts, preserve planned dose intensity, and reduce Grade 3–4 thrombocytopenia following gemcitabine and platinum chemotherapy. These findings are consistent with A(1–7)-induced stimulation of thrombogenesis in the bone marrow following marrow-toxic chemotherapy.