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Post-hemorrhagic shock mesenteric lymph (PHSML) return plays a critical role in the development of acute kidney injury (AKI). However, the molecular mechanism underlying PHSML-mediated AKI remains unclear. In this study, bioinformatics analysis identified key common targets of hemorrhagic shock and AKI, revealing significant enrichment in the renin-angiotensin system (RAS). To further investigate the role of RAS in PHSML-mediated AKI, we established mesenteric lymph duct ligation (MLDL) technology in mice and confirmed that MLDL alleviated hemorrhagic shock-induced AKI. Subsequently, male C57BL/6 mice subjected to hemorrhagic shock were treated with the angiotensin converting enzyme (ACE) inhibitor enalapril, angiotensin (1-7) (Ang (1-7)), and angiotensin II (Ang II) type 1 receptor (AT1R) inhibitor losartan. Additionally, mice with hemorrhage and MLDL were treated with Ang II, the Mas receptor (MasR) inhibitor A-779, or subjected to Ace2 knockout. Renal histomorphology, expression of ACE, ACE2, AT1R, and MasR, and levels of Ang II and Ang (1-7) were assessed 4 h after resuscitation. The results demonstrated that hemorrhagic shock upregulated ACE and AT1R, while downregulating ACE2 and MasR, accompanied by elevated Ang II and reduced Ang (1-7). These adverse effects were partially reversed by MLDL, enalapril, Ang-(1-7), or losartan. Conversely, the beneficial role of MLDL was abolished by Ace2 deficiency and the administration of Ang II and A-779. Collectively, these findings indicate that disequilibrium between the ACE-AngII-AT1R and ACE2-Ang (1-7)-MasR axes is implicated in PHSML-mediated AKI.

Aims To investigate the effect of the angiotensin peptides and their agonists and antagonists on cellular proliferation in proliferating infantile haemangioma (IH) in vitro explants. Methods Proliferating IH samples from six patients were cultured in vitro in the presence of angiotensin I (ATI) alone, or AT1 and the ACE inhibitor, ramipril, or ATII alone, or ATII with the ATII receptor 1 (ATIIR1) blocker, losartan, or ATII with the ATIIR2 blocker, PD123319, or the ATIIR2 agonist, CGP42112. After 6 days in culture, the IH tissue pieces were harvested, formalin-fixed and paraffin-embedded. The effect of each treatment type on cellular proliferation was evaluated by immunohistochemical staining of these tissue pieces using the proliferation marker, Ki67. Results There was a significant increase in cellular proliferation in the ATI and ATII treated IH tissues compared with control samples. Their effect on cellular proliferation was reduced by adding ramipril and PD123319, respectively. CGP42112, but not losartan, significantly increased cellular proliferation. Conclusions Our findings suggest a key regulatory role of ATI and ATII in promoting cellular proliferation in IH, and establish a role for ACE and ATIIR2 in the proliferation of this tumour.

Accumulating evidence suggests a cardioprotective role of pacing postconditioning (PPC) maneuvers in animal models and more recently in humans. The procedure however remains to be optimized and its interaction with physiological systems remains to be further explored. The renin angiotensin system (RAS) plays a dual role in ischemia/reperfusion (I/R) injury. The interaction between RAS and PPC induced cardiac protection is however not clearly understood. We have recently demonstrated that angiotensin (1-7) via Mas receptor played a significant role in PPC mediated cardiac protection against I/R injury. The objective of this study was to investigate the role of angiotensin converting enzyme (ACE)-chymase-angiotensin II (Ang II)-angiotensin receptor 1 (AT1) axes of RAS in PPC mediated cardiac protection. Isolated rat hearts were subjected to I/R (control) or PPC in the presence or absence of Ang II, chymostatin (inhibitor of locally produced Ang II), ACE blocker (captopril) or AT1 antagonist (irbesartan). Hemodynamics data was computed digitally and infarct size was determined histologically using TTC staining and biochemically by measuring creatine kinase (CK) and lactate dehydrogenase levels. Cardiac hemodynamics were significantly (P<0.001) improved and infarct size and cardiac enzymes were significantly (P<0.001) reduced in hearts subjected to PPC relative to hearts subjected to I/R injury. Exogenous administration of Ang II did not affect I/R injury or PPC mediated protection. Nonetheless inhibition of endogenously synthesized Ang II protected against I/R induced cardiac damage yet did not block or augment the protective effects of PPC. The administration of AT1 antagonist did not alleviate I/R induced damage. Interestingly it abrogated PPC induced cardiac protection in isolated rat hearts. Finally, PPC induced protection and blockade of locally produced Ang II involved enhanced activation of ERK1/2 and Akt components of the reperfusion injury salvage kinase (RISK) pathway. This study demonstrate a novel role of endogenously produced Ang II in mediating I/R injury and highlights the significance of AT1 signaling in PPC mediated cardiac protection in isolated rodents hearts ex vivo. The interaction between Ang II-AT1 and PPC appears to involve alterations in the activation state of ERK1/2 and Akt components of the RISK pathway.

The renin-angiotensin system (RAS) is activated in aortic valve disease, yet little is understood about how it affects the acute functional response of valve interstitial cells (VICs). Herein, we developed a gelatin-based valve thin film (vTF) platform to investigate whether the contractile response of VICs can be regulated via RAS mediators and inhibitors. First, the impact of culture medium (quiescent, activated, and osteogenic medium) on VIC phenotype and function was assessed. Contractility of VICs was measured upon treatment with angiotensin I (Ang I), angiotensin II (Ang II), angiotensin-converting enzyme (ACE) inhibitor, and Angiotensin II type 1 receptor (AT1R) inhibitor. Anisotropic cell alignment on gelatin vTF was achieved independent of culture conditions. Cells cultured in activated and osteogenic conditions were found to be more elongated than in quiescent medium. Increased α-SMA expression was observed in activated medium and no RUNX2 expression were observed in cells. VIC contractile stress increased with increasing concentrations (from 10−10 to 10−6 M) of Ang I and Ang II. Moreover, cell contraction was significantly reduced in all ACE and AT1R inhibitor-treated groups. Together, these findings suggest that local RAS is active in VICs, and our vTF may provide a powerful platform for valve drug screening and development.

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.

The renin–angiotensin system (RAS) is the main endocrine and tissular component responsible for controlling cardiovascular homeostasis, which can be modulated by estrogen levels. This study investigated the effects of hormone treatments with estrogen and progestins on angiotensin-(1-7)-mediated [Ang-(1-7)] vasodilation in ovariectomized rats and the possible mechanisms involving the RAS. Female Wistar rats were divided into the following groups: sham (SHAM), ovariectomized (OVX), OVX and treated with 17β-estradiol (E2) (OE2), OVX and treated with E2 and drospirenone (OE2 + DRSP), and OVX and treated with medroxyprogesterone (MPA). Hormonal treatment was delivered via gavage for 28 days. Vascular responses to Ang-(1-7) were assessed in isolated aortic rings, and a Western blot of the thoracic aorta was used to determine the protein levels of angiotensin II (Ang II) type-1 receptor (AT1R), Ang II type-2 receptor (AT2R), Ang-(1-7) receptor (Mas), angiotensin-converting enzyme 2 (ACE2), and endothelial nitric oxide synthase (eNOS). The results showed impaired vascular reactivity caused by ovariectomy. Ang-(1-7) induced vasodilation in the OE2, OE2 + DRSP, and MPA-treated groups, while the administration of the AT2R antagonist (PD123319) or the selective Mas antagonist (A779) increased the extent of vasorelaxation induced by Ang-(1-7) in the OVX + MPA group. There were no differences in the aortic levels of AT1R or ACE2 between the groups, but the MPA group showed significantly increased levels of AT2R and eNOS. We concluded that ovariectomy induced vascular dysfunction linked to RAS regulation, and both estrogen (E2) and progestins differentially restored these parameters.

Compound 21 (C21), an AT2 receptor agonist, and Angiotensin 1-7 (Ang 1-7), through Mas receptor, play an important role in the modulation of the protective arm of the renin-angiotensin system. The aim of this study was to investigate in an experimental model of angiotensin II-dependent hypertension whether the activation of the potentially protective arm of the renin-angiotensin system, through AT2 or Mas receptor stimulation, counteracts the onset of myocardial fibrosis and hypertrophy, and whether these effects are mediated by inflammatory mechanism and/or sympathetic activation. Sprague Dawley rats (n = 67) were treated for 1 (n = 25) and 4 (n = 42) weeks and divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis); (b) Ang II+Compound 21 (C21, 0.3 mg/kg/day, intraperitoneal); (c) Ang II+Ang 1-7 (576 µg/kg/day, intraperitoneal); (d) Ang II+Losartan (50 mg/kg/day, per os); (e) control group (physiological saline, sub cutis). Systolic blood pressure was measured by tail cuff method and, at the end of the experimental period, the rats were euthanized and the heart was excised to evaluate myocardial fibrosis, hypertrophy, inflammatory cell infiltration and tyrosine hydroxylase expression, used as marker of sympathetic activity. Ang II caused a significant increase of blood pressure, myocardial interstitial and perivascular fibrosis and myocardial hypertrophy, as compared to control groups. C21 or Ang 1-7 administration did not modify the increase in blood pressure in Ang II treated rats, but both prevented the development of myocardial fibrosis and hypertrophy. Treatment with losartan blocked the onset of hypertension and myocardial fibrosis and hypertrophy in Ang II treated rats. Activation of AT2 receptors or Mas receptors prevents the onset of myocardial fibrosis and hypertrophy in Ang II-dependent hypertension through the reduction of myocardial inflammatory cell infiltration and tyrosine hydroxylase expression. Unlike what happens in case of treatment with losartan, the antifibrotic and antihypertrophic effects that follow the activation of the AT2 or Mas receptors are independent on the modulation of blood pressure.

SARS-CoV-2 infection is mediated by the binding of its spike protein to the angiotensin-converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The study of RAS dysregulation due to SARS-CoV-2 infection is fundamentally important for a better understanding of the pathogenic mechanisms and risk factors associated with COVID-19 coronavirus disease and to design effective therapeutic strategies. In this context, we developed a mathematical model of RAS based on data regarding protein and peptide concentrations; the model was tested on clinical data from healthy normotensive and hypertensive individuals. We used our model to analyze the impact of SARS-CoV-2 infection on RAS, which we modeled through a downregulation of ACE2 as a function of viral load. We also used it to predict the effect of RAS-targeting drugs, such as RAS-blockers, human recombinant ACE2, and angiotensin 1–7 peptide, on COVID-19 patients; the model predicted an improvement of the clinical outcome for some drugs and a worsening for others. Our model and its predictions constitute a valuable framework for in silico testing of hypotheses about the COVID-19 pathogenic mechanisms and the effect of drugs aiming to restore RAS functionality.

Neuroinflammation is associated with activation of glial cells and pro-inflammatory arm of the central Renin Angiotensin System (RAS) namely, Angiotensin-Converting Enzyme/Angiotensin II/Angiotensin Type 1 Receptor (ACE/Ang II/AT1R) axis. Apart from this, another axis of RAS also exists, Angiotensin-Converting Enzyme 2/Angiotensin (1–7)/Mas Receptor (ACE2/Ang (1–7)/MasR), which counters ACE/Ang II/AT1R axis by showing anti-inflammatory properties. However, the role of ACE2/Ang (1–7)/MasR axis has not been explored in glial activation and neuroinflammation. Hence, the present study tries to unveil the role of ACE2/Ang (1–7)/MasR axis in lipopolysaccharide (LPS)-induced neuroinflammation using diminazene aceturate (DIZE), an ACE2 activator, in astroglial (C6) and microglial (BV2) cells as well as male SD rats. We found that ACE2 activation efficiently prevented LPS-induced changes by decreasing glial activation, inflammatory signaling, cell migration, ROS generation via upregulation of ACE2/Ang (1–7)/MasR signaling. In addition, activation of ACE2/Ang (1–7)/MasR axis by DIZE significantly suppressed the pro-inflammatory ACE/Ang II/AT1R axis by reducing Ang II level in neuroinflammatory conditions induced by LPS in both in vitro and in vivo. ACE2/Ang (1–7)/MasR axis activation further decreased mitochondrial depolarization and apoptosis, hence providing neuroprotection. Furthermore, to validate that the beneficial effect of the ACE2 activator was indeed through MasR, a selective MasR antagonist (A779) was used that significantly blocked the anti-inflammatory effect of ACE2 activation by DIZE. Hence, our study demonstrated that ACE2 activation imparted neuroprotection by enhancing ACE2/Ang (1–7)/MasR signaling which in turn decreased glial activation, neuroinflammation, and apoptosis and improved mitochondrial health. Graphical abstract

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.