Diverse biological functions of the renin-angiotensin system.

The renin-angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS-inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.

Angiotensin-(1-7) plays an important role in regulating spermatogenesis in Trachemys scripta elegans under salinity stress.

Elevation in water salinity can threaten the spermatogenesis and fertility of freshwater animals. The role of the renin-angiotensin system (RAS) in regulating spermatogenesis has attracted considerable attention. Our previous study found that red-eared sliders (Trachemys scripta elegans), could survive in 10 PSU water for over 1 year. To understand the chronic impact of salinity on testicular spermatogenesis and underlying mechanisms, male T. s. elegans were subjected to treatment with water of 5 PSU and 10 PSU for a year, and spermatogenesis and regulation of the RAS signal pathway was assessed. Results showed induced inflammation in the testes of T. s. elegans in the 10 PSU group, as evidenced by a decrease in the number of testicular germ cells from 1586 to 943. Compared with the control group, the levels of proinflammatory genes, including TNF-α, IL-12A and IL-6 were elevated 3.1, 0.3, and 1.4 times, respectively, in animals exposed to 10 PSU water. Testicular antiapoptotic processes of T. s. elegans might involve the vasoactive peptide angiotensin-(1-7) in the RAS, as its level was significantly increased from 220.2 ng ml-1 in controls to 419.2 ng ml-1 in the 10 PSU group. As expected, specific inhibitor (A-779) for the Ang-(1-7) acceptor effectively prevented the salinity-induced upregulation of genes encoding anti-inflammatory and antiapoptotic factors (TGF-ß1, Bcl-6) in the testis of the 10 PSU animals, whereas it promoted the upregulation of proinflammatory and proapoptotic factors (TNF-α, IL-12A, IL-6, Bax and caspase-3). Our data indicated that Ang-(1-7) attenuates the effect of salinity on inflammation and apoptosis of the testis in T. s. elegans. A new perspective to prevent salinity-induced testis dysfunction is provided.

A single dose of angiotensin-(1-7) resolves eosinophilic inflammation and protects the lungs from a secondary inflammatory challenge.

OBJECTIVE: Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator. It is not known whether the pro-resolving effects of Ang-(1-7) are sustained and protect the lung from a subsequent inflammatory challenge. This study sought to investigate the impact of treatment in face of a second allergic or lipopolysaccharide (LPS) challenge. METHODS: Mice, sensitized and challenged with ovalbumin (OVA), received a single Ang-(1-7) dose at the peak of eosinophilic inflammation, 24 h after the final OVA challenge. Subsequently, mice were euthanized at 48, 72, 96, and 120 h following the OVA challenge, and cellular infiltrate, inflammatory mediators, lung histopathology, and macrophage-mediated efferocytic activity were evaluated. The secondary inflammatory stimulus (OVA or LPS) was administered 120 h after the last OVA challenge, and subsequent inflammatory analyses were performed. RESULTS: Treatment with Ang-(1-7) resulted in elevated levels of IL-10, CD4+Foxp3+, Mres in the lungs and enhanced macrophage-mediated efferocytic capacity. Moreover, in allergic mice treated with Ang-(1-7) and then subjected to a secondary OVA challenge, inflammation was also reduced. Similarly, in mice exposed to LPS, Ang-(1-7) effectively prevented the lung inflammation. CONCLUSION: A single dose of Ang-(1-7) resolves lung inflammation and protect the lung from a subsequent inflammatory challenge highlighting its potential therapeutic for individuals with asthma.

Angiotensin-(1-7) ameliorates intestinal barrier dysfunction by activating the Keap1/Nrf2/HO-1 signaling pathway in acute pancreatitis.

BACKGROUND: Intestinal barrier dysfunction is a serious complication associated with acute pancreatitis (AP). Angiotensin (Ang)-(1-7) plays a protective role in the intestinal barrier, but the underlying mechanism remains clear. This study investigated the impact of Ang-(1-7) on AP-induced intestinal dysfunction and its involvement in the Keap1/Nrf2/HO-1 pathway. METHODS AND RESULTS: We studied caerulein- and lipopolysaccharide (LPS)-induced AP in mice and an epithelial cell line (IEC-6) from the small intestinal crypt of rats. Ang-(1-7) was administered orally or via the tail vein. IEC-6 cells were divided into five groups: control; LPS; LPS + Ang-(1-7); LPS + Ang-(1-7) + ML385 (an Nrf2 inhibitor); and LPS + ML385. Pancreatic and intestinal histopathology scores were analyzed using the Schmidt and Chiu scores. The expression of intestinal barrier-associated proteins and Keap1/Nrf2/HO-1 pathway constituents was assessed by RT-PCR and western blotting. The peroxide and antioxidant activities in the IEC-6 cells were measured. Compared to those in AP mice, Ang-(1-7) diminished the intestinal levels of proinflammatory factors (interleukin-1ß and tumor necrosis factor α) and serum levels of intestine permeability (D-lactate). Ang-(1-7) increased the expression of barrier-associated proteins (aquaporin-1, claudin-1, and occludin) compared to those in the AP and LPS group. Moreover, Ang-(1-7) promoted the Keap/Nrf2/HO-1 pathway, which resulted in significantly reduced malondialdehyde and increased superoxide dismutase levels.. However, ML385 abolished the effects of Ang-(1-7) on barrier-associated proteins and reversed the Keap1/Nrf2/HO-1 pathway. CONCLUSIONS: Ang-(1-7) reduces AP-induced intestinal inflammation and oxidative injuries by activating the Keap1/Nrf2/HO-1 pathway.

The alternative renin-angiotensin-system (RAS) signalling pathway in prostate cancer and its link to the current COVID-19 pandemic.

BACKGROUND: The renin-angiotensin system is known to maintain blood pressure and body fluids. However, it has been found to consist of at least two major constituents, the classic and the alternative pathway, balancing and supporting each other's signalling in a very intricate way. Current research has shown that the renin-angiotensin system is involved in a broad range of biological processes and diseases, such as cancer and infectious diseases. METHODS AND RESULTS: We conducted a literature review on the interaction of the renin-angiotensin system and prostate cancer and explored the research on the possible impact of the SARS-CoV-2 virus in this context. This review provides an update on contemporary knowledge into the alternative renin-angiotensin system, its role in cancer, specifically prostate cancer, and the implications of the current COVID-19 pandemic on cancer and cancer care. CONCLUSION: In this work, we aim to demonstrate how shifting the RAS signalling pathway from the classic to the alternative axis seems to be a viable option in supporting treatment of specific cancers and at the same time demonstrating beneficial properties in supportive care. It however seems to be the case that the infection with SARS-CoV-2 and subsequent impairment of the renin-angiotensin-system could exhibit serious deleterious long-term effects even in oncology.

Neuroprotective effect of canagliflozin against cisplatin-induced cerebral cortex injury is mediated by regulation of HO-1/PPAR-γ, SIRT1/FOXO-3, JNK/AP-1, TLR4/iNOS, and Ang II/Ang 1-7 signals.

OBJECTIVES: Canagliflozin (CAN), a sodium-glucose co-transporter 2 inhibitor, is an anti-hyperglycemic drug that has been approved to treat diabetes. This study evaluated the beneficial effects of CAN on cerebral cortex intoxication induced by cisplatin (CIS). MATERIALS AND METHODS: Rats were allocated into four groups: normal control, CAN (10 mg/kg, P.O.) for 10 days, CIS (8 mg/kg, i.p.) as a single dose on the 5th day of the experiment, and CAN + CIS group. RESULTS: In comparison with CIS control rats, CAN significantly mitigated CIS-induced cortical changes in rats' behavior in the open field and forced swimming assessment as well as histological structure. Biochemically, CAN administration efficiently decreased lipid peroxidation biomarkers MDA and boosted the antioxidant status via a remarkable increase in the cortical reduced glutathione (GSH) content as well as enzymatic activities of antioxidant enzymes superoxide dismutase (SOD), glutathione-S-transferase (GST), catalase (CAT), and glutathione peroxidase (GPx) mediated by up-regulation of heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptors (PPARγ), and silent information regulator (SIRT1)/forkhead box-O3 (FOXO-3) signals. Additionally, pretreatment with CAN significantly decreased cortical myeloperoxidase (MPO), nitrite (NO2-), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels. At the same time, it elevated the IL-10 level associated with the downregulation of Jun N-terminal kinase (JNK)/activator protein 1 (AP-1), TLR4/inducible nitric oxide synthase (iNOS)/nitric oxide (NO), and Ang II/Ang 1-7 signals. CONCLUSIONS: Due to the potent antioxidant and anti-inflammatory properties of CAN, our findings showed that CAN could be a good candidate for the protection against CIS-induced cortical intoxication in the patient receiving CIS.

All-trans retinoic acid inhibits oxidative stress via ACE2/Ang (1-7)/MasR pathway in renal tubular epithelial cells stimulated with high glucose.

The aim of this study was to investigate the effects of all-trans retinoic acid (atRA) on oxidative stress in renal tubular epithelial cells induced by high glucose (HG) and its potential mechanism. We investigated the effects of atRA in HG-induced renal epithelial cell line HK-2. Seven groups were designed for this experiment: negative control, mannitol, high-glucose (HG), HG combined with a low concentration of atRA, HG combined with a middle concentration of atRA, HG combined with a high concentration of atRA, and HG combined with captopril. After 48 h of incubation, oxidative stress factor expression in the supernatant was detected by enzyme-linked immunosorbent assay. Reactive oxygen species and cell apoptosis expression were assessed by flow cytometry. NADPH oxidase, fibrosis factor, and angiotensin-converting enzyme 2/angiotensin (1-7)/mas receptor (ACE2/Ang (1-7)/MasR) pathway-related protein expressions were determined by western blot analysis. The expressions of oxidative stress factors, NADPH oxidase components, and fibrosis factors were significantly higher after HG treatment. Apoptosis of HK2 cells in the HG group was also significantly higher. AtRA could reverse the above abnormal changes in a concentration-dependent manner. HG significantly promoted the expression of ACE, Ang II, and Ang II type 1 receptor (AT1R), whereas it inhibited the expression of ACE2, Ang (1-7), and MasR. With the elevation of concentration, atRA could gradually suppress the expression of ACE, Ang II, and AT1R, but facilitate ACE2, Ang (1-7), and MasR. These results were statistically significant. AtRA could significantly inhibit oxidative stress and apoptosis of renal tubular epithelial cells induced by HG. The mechanism may inhibit the ACE/Ang II/AT1R pathway and/or activate ACE2/Ang (1-7)/MasR pathway.

Balancing renal Ang-II/Ang-(1-7) by xanthenone; an ACE2 activator; contributes to the attenuation of Ang-II/p38 MAPK/NF-κB p65 and Bax/caspase-3 pathways in amphotericin B-induced nephrotoxicity in rats.

Despite the great importance of amphotericin B for the management of life-threatening systemic fungal infections, its nephrotoxic effect restricts its repeated administration. This study was designed to examine the prospective modulatory effects of xanthenone, an ACE2 activator, against amphotericin B nephrotoxicity. Male Wistar rats were allocated into four groups; control (1st), Xanthenone (2nd), Amphotericin B (3rd), and Xanthenone + Amphotericin B (4th). The second and fourth groups received xanthenone (2 mg/kg; s.c.) daily for 14 consecutive days. Amphotericin B (18.5 mg/kg; i.p.) was administered to the third and fourth groups daily starting from day 8. After 2 weeks, samples were withdrawn for analysis. The histopathological findings, molecular and biochemical markers showed that amphotericin B caused marked renal injury. Pretreatment with xanthenone ameliorated amphotericin B-induced deterioration in kidney function biomarkers (creatinine, urea, cystatin C, KIM-1) and guarded against the disturbance of serum electrolytes (Na+, K+, Mg2+) due to amphotericin B-induced tubular dysfunction. Besides, the ACE2 activator xanthenone-balanced renal Ang-II/Ang-(1-7), and so the inflammatory signaling p38 MAPK/NF-κB p65 and its downstream inflammatory cytokines (TNF-α, IL-6) were attenuated. Meanwhile, the anti-oxidant signaling Nrf2/HO-1 and glutathione content were preserved, but the lipid peroxidation marker MDA was declined. These regulatory effects of xanthenone eventually enhanced Bcl-2 (anti-apoptotic), but reduced Bax (pro-apoptotic) and cleaved caspase-3 (apoptotic executioner) protein expressions. Collectively, the regulatory effects of xanthenone on renal Ang-II/Ang-(1-7) could at least partially contribute to the mitigation of amphotericin B nephrotoxicity by attenuating inflammatory signaling, oxidative stress, and apoptosis, thus improving the tolerability to amphotericin B.

Angiotensin-converting enzyme 2 identifies immuno-hot tumors suggesting angiotensin-(1-7) as a sensitizer for chemotherapy and immunotherapy in breast cancer.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is known as a tumor suppressor and lowly expressed in most cancers. The expression pattern and role of ACE2 in breast cancer (BC) have not been deeply elucidated. METHODS: A systematic pan-cancer analysis was conducted to assess the expression pattern and immunological role of ACE2 based on RNA-sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas (TCGA). The correlation of ACE2 expression and immunological characteristics in the BC tumor microenvironment (TME) was evaluated. The role of ACE2 in predicting the response to therapeutic options was estimated. Moreover, the pharmacodynamic effect of angiotensin-(1-7) (Ang-1-7), the product of ACE2, on chemotherapy and immunotherapy was evaluated on the BALB/c mouse BC model. In addition, the plasma samples from BC patients receiving neoadjuvant chemotherapy were collected and subjected to the correlation analysis of the expression level of Ang-1-7 and the response to neoadjuvant chemotherapy. RESULTS: ACE2 was lowly expressed in BC tissues compared with that in adjacent tissues. Interestingly, ACE2 was shown the highest correlation with immunomodulators, tumor-infiltrating immune cells (TIICs), cancer immunity cycles, immune checkpoints, and tumor mutation burden (TMB) in BC. In addition, a high level of ACE2 indicated a low response to endocrine therapy and a high response to chemotherapy, anti-ERBB therapy, antiangiogenic therapy and immunotherapy. In the mouse model, Ang-1-7 sensitized mouse BC to the chemotherapy and anti-PD-1 immunotherapy, which revealed its significant anti-tumor effect. Moreover, a high plasma level of Ang-1-7 was associated with a better response to neoadjuvant chemotherapy. CONCLUSIONS: ACE2 identifies immuno-hot tumors in BC, and its enzymatic product Ang-1-7 sensitizes BC to the chemotherapy and immunotherapy by remodeling the TME.

Angiotensin-(1-7) promotes mitochondrial translocation of human telomerase reverse transcriptase in HUVECs through the TOM20 complex.

BACKGROUND: Angiotensin (Ang) (1-7) is a vasodilator peptide that ameliorates microcirculation dysfunction, increases telomerase activity in cells, and exerts vasodilatory, anti-inflammatory, antioxidative stress, and antiapoptotic effects. Mitochondrial human telomerase reverse transcriptase (hTERT) plays an important role in the processes of antiapoptosis, antioxidative stress, and immortalization. This study aimed to investigate the effect of Ang(1-7) on the mitochondrial translocation of hTERT. METHODS: An in vitro model of lipopolysaccharide (LPS)-induced inflammation was established in human umbilical vein endothelial cells (HUVECs). Ang(1-7) was added to cells 30 min before LPS stimulation. The Ang(1-7)/Mas receptor antagonist A779 plus Ang(1-7) were added to the cells 30 min before LPS stimulation. The translocase outer membrane (TOM)20-overexpression HUVECs (HUVEC-TOM20OE), TOM20-knockdown HUVECs (HUVEC-TOM20KD), and the corresponding negative control cell lines were constructed by lentiviral transfection of HUVECs. Cells subjected to LPS stimulation alone, LPS plus Ang(1-7), LPS plus Ang(1-7) and A779, vehicle and no treatment were termed the LPS group, LPS + A group, LPS + A + A779 group, Con group and Neg group, respectively. Immunofluorescence staining was used to detect the distribution of hTERT in the nuclei and mitochondria of HUVECs and to locate TOM20, TOM40, and translocase inner membrane (TIM)23 in the mitochondria. The protein expression levels of total hTERT, mitochondrial hTERT, TOM20, TOM40, and TIM23 were measured by Western blot. The mRNA expression levels of hTERT, TOM20, TOM40, and TIM23 were assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: hTERT colocalized with TOM40, TOM20 and TIM23 in the mitochondria. The mitochondrial hTERT protein level of the LPS + A group was significantly greater than that of the LPS group (P = 0.001), and the LPS group showed significantly increased expression of mitochondrial hTERT compared with that of the control group (P = 0.001). No significant difference in the level of total hTERT was observed between the LPS + A and LPS groups. The mitochondrial hTERT protein level of the LPS + A + A779 group was significantly lower than that of the LPS + A group (P = 0.021). The protein level of mitochondrial hTERT in HUVEC-TOM20KD treated with or without LPS alone or LPS + A was significantly decreased compared with the corresponding groups of control HUVECs (HUVEC-TOM20KD-Con vs. HUVEC-Con, P = 0.035; HUVEC-TOM20KD-LPS vs. HUVEC-LPS, P = 0.003; HUVEC-TOM20KD-LPS + A vs. HUVEC-LPS + A, P = 0.001), and treatment with Ang(1-7) did not restore the downregulation of mitochondrial hTERT in HUVEC-TOM20KD. HUVEC-TOM20OE showed a significantly increased level of mitochondrial hTERT (HUVEC-TOM20OE-Con vs. HUVEC-Con, P = 0.010), which was further elevated by Ang(1-7) stimulation (HUVEC-TOM20OE-LPS + A vs. HUVEC-TOM20OE-Con, P = 0.011). Lastly, the protein expression levels of TOM40 (HUVEC-TOM20KD-Con vs. HUVEC-Con, P = 0.007) and TIM23 (HUVEC-TOM20KD-Con vs. HUVEC-Con, P = 0.001) were significantly increased in HUVEC-TOM20KD in comparison to HUVECs. CONCLUSIONS: Ang(1-7) effectively promoted mitochondrial translocation of hTERT in HUVECs via TOM20, indicating that hTERT may be transported to the mitochondria through the TOM20 complex. In addition, A779 could block the effects of Ang(1-7) in HUVECs.

Unveiling the G4-PAMAM capacity to bind and protect Ang-(1-7) bioactive peptide by molecular dynamics simulations.

Angiotensin-(1-7) re-balance the Renin-Angiotensin system affected during several pathologies, including the new COVID-19; cardiovascular diseases; and cancer. However, one of the limiting factors for its therapeutic use is its short half-life, which might be overcome with the use of dendrimers as nanoprotectors. In this work, we addressed the following issues: (1) the capacity of our computational protocol to reproduce the experimental structural features of the (hydroxyl/amino)-terminated PAMAM dendrimers as well as the Angiotensin-(1-7) peptide; (2) the coupling of Angiotensin-(1-7) to (hydroxyl/amino)-terminated PAMAM dendrimers in order to gain insight into the structural basis of its molecular binding; (3) the capacity of the dendrimers to protect Angiotensin-(1-7); and (4) the effect of pH changes on the peptide binding and covering. Our Molecular-Dynamics/Metadynamics-based computational protocol well modeled the structural experimental features reported in the literature and our double-docking approach was able to provide reasonable initial structures for stable complexes. At neutral pH, PAMAM dendrimers with both terminal types were able to interact stably with 3 Angiotensin-(1-7) peptides through ASP1, TYR4 and PRO7 key amino acids. In general, they bind on the surface in the case of the hydroxyl-terminated compact dendrimer and in the internal zone in the case of the amino-terminated open dendrimer. At acidic pH, PAMAM dendrimers with both terminal groups are still able to interact with peptides either internalized or in its periphery, however, the number of contacts, the percentage of coverage and the number of hydrogen bonds are lesser than at neutral pH, suggesting a state for peptide release. In summary, amino-terminated PAMAM dendrimer showed slightly better features to bind, load and protect Angiotensin-(1-7) peptides.

Research Progress on Pulmonary Arterial Hypertension and the Role of the Angiotensin Converting Enzyme 2-Angiotensin-(1-7)-Mas Axis in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease with a complex aetiology and high mortality. Functional and structural changes in the small pulmonary arteries lead to elevated pulmonary arterial pressure, resulting in right heart failure. The pathobiology of PAH is not fully understood, and novel treatment targets in PAH are desperately needed. The renin-angiotensin system is critical for maintaining homeostasis of the cardiovascular system. The system consists of the angiotensin converting enzyme (ACE)-angiotensin (Ang) II-angiotensin type 1 receptor (AT1R) axis and the ACE2-Ang-(1-7)-Mas receptor axis. The former, the ACE-Ang II-AT1R axis, is involved in vasoconstrictive and hypertensive actions along with cardiac and vascular remodelling. The latter, the ACE2-Ang-(1-7)-Mas axis, generally mediates counterbalancing effects against those mediated by the ACE-Ang II-AT1R axis. Based on established functions, the ACE2-Ang-(1-7)-Mas axis may represent a novel target for the treatment of PAH. This review focuses on recent advances in pulmonary circulation science and the role of the ACE2-Ang-(1-7)-Mas axis in PAH.

Role of Ang1-7 in renal haemodynamics and excretion in streptozotocin diabetic rats.

The contribution of angiotensin (1-7) (Ang1-7) to control of extrarenal and renal function may be modified in diabetes. We investigated the effects of Ang1-7 supplementation on blood pressure, renal circulation and intrarenal reactivity (IVR) to vasoactive agents in normoglycaemic (NG) and streptozotocin diabetic rats (DM). In Sprague Dawley DM and NG rats, 3 weeks after streptozotocin (60 mg/kg i.p.) or solvent injection, Ang1-7 was administered (400 ng/min) over the next 2 weeks using subcutaneously implanted osmotic minipumps. For a period of 5 weeks, blood pressure (BP), 24 h water intake and diuresis were determined weekly. In anaesthetised rats, BP, renal total and cortical (CBF), outer (OMBF) and inner medullary (IMBF) perfusion and urine excretion were determined. To check IVR, a short-time infusion of acetylcholine or norepinephrine was randomly given to the renal artery. Unexpectedly, BP did not differ between NG and DM, and this was not modified by Ang-1-7 supplementation. Baseline IMBF was higher in NG vs. DM, and Ang1-7 treatment did not change it in NG but decreased it in DM. In the latter, Ang1-7 increased cortical IVR to vasoconstrictor and vasodilator stimuli. IMBF decrease after high acetylcholine dose seen in untreated NG was reverted to an increase in Ang1-7 treated rats. Irrespective of the glycaemia level, Ang1-7 did not modify BP. However, it impaired medullary circulation in DM, whereas in NG it rendered the medullary vasculature more sensitive to vasodilators. Possibly, the medullary hypoperfusion in DM was mediated by Ang1-7 activation of angiotensin AT-1 receptors which are upregulated by hyperglycaemia.

Blockade of endothelial Mas receptor restores the vasomotor response to phenylephrine in human resistance arterioles pretreated with captopril and exposed to propofol.

BACKGROUND: Hypotension that is resistant to phenylephrine is a complication that occurs in anesthetized patients treated with angiotensin converting enzyme (ACE) inhibitors. We tested the hypothesis that Ang 1-7 and the endothelial Mas receptor contribute to vasodilation produced by propofol in the presence of captopril. METHODS: The internal diameters of human adipose resistance arterioles were measured before and after administration of phenylephrine (10-9 to 10-5 M) in the presence and absence of propofol (10-6 M; added 10 min before the phenylephrine) or the Mas receptor antagonist A779 (10-5 M; added 30 min before phenylephrine) in separate experimental groups. Additional groups of arterioles were incubated for 16 to 20 h with captopril (10-2 M) or Ang 1-7 (10-9 M) before experimentation with phenylephrine, propofol, and A779. RESULTS: Propofol blunted phenylephrine-induced vasoconstriction in normal vessels. Captopril pretreatment alone did not affect vasoconstriction, but the addition of propofol markedly attenuated the vasomotor response to phenylephrine. A779 alone did not affect vasoconstriction in normal vessels, but it restored vasoreactivity in arterioles pretreated with captopril and exposed to propofol. Ang 1-7 reduced the vasoconstriction in response to phenylephrine. Addition of propofol to Ang 1-7-pretreated vessels further depressed phenylephrine-induced vasoconstriction to an equivalent degree as the combination of captopril and propofol, but A779 partially reversed this effect. CONCLUSIONS: Mas receptor activation by Ang 1-7 contributes to phenylephrine-resistant vasodilation in resistance arterioles pretreated with captopril and exposed to propofol. These data suggest an alternative mechanism by which refractory hypotension may occur in anesthetized patients treated with ACE inhibitors.

Renin-angiotensin system modulators in COVID-19 patients with hypertension: friend or foe?

Background: ACE2, a component of the non-classic renin-angiotensin system (RAS), acts as a functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) spike protein, which enables the entry of the virus into the host cells. Non-classical ACE2 is one of two types of ACE2 that has a protective effect on vascular and respiratory cells. RAS modulators like angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are among the first-line treatment for hypertensive patients. An upregulation in ACE2 levels with RAS modulators was observed in few preclinical studies, which raised concerns regarding possible increased infectivity among patients treated with RAS modulators.Method: For shortlisting the outcome effects, open-ended, English-restricted databases, published literature, and various clinical studies performed utilizing RAS modulators in COVID 19 patients were considered. Conclusion: Current evidence reveals no increased risk of COVID-19 infection among hypertensive patients on ACEIs/ARBs compared to other antihypertensive medications. Several studies have demonstrated no detrimental effects of RAS modulators on clinical severity, hospital/intensive care unit stay, ventilation and mortality.  Hence, we can conclude that neither ARBs nor ACEIs treatment will cause any side effects or undesirable interactions in COVID-19 infected hypertensive patients.

Treatment with Angiotensin-(1-7) Prevents Development of Oral Papilloma Induced in K-ras Transgenic Mice.

Oral Squamous Cell Carcinoma (OSCC) is the most common malignant cancer affecting the oral cavity. It is characterized by high morbidity and very few therapeutic options. Angiotensin (Ang)-(1-7) is a biologically active heptapeptide, generated predominantly from AngII (Ang-(1-8)) by the enzymatic activity of angiotensin-converting enzyme 2 (ACE 2). Previous studies have shown that Ang-(1-7) counterbalances AngII pro-tumorigenic actions in different pathophysiological settings, exhibiting antiproliferative and anti-angiogenic properties in cancer cells. However, the prevailing effects of Ang-(1-7) in the oral epithelium have not been established in vivo. Here, we used an inducible oral-specific mouse model, where the expression of a tamoxifen-inducible Cre recombinase (CreERtam), which is under the control of the cytokeratin 14 promoter (K14-CreERtam), induces the expression of the K-ras oncogenic variant KrasG12D (LSLK-rasG12D). These mice develop highly proliferative squamous papilloma in the oral cavity and hyperplasia exclusively in oral mucosa within one month after tamoxifen treatment. Ang-(1-7) treated mice showed a reduced papilloma development accompanied by a significant reduction in cell proliferation and a decrease in pS6 positivity, the most downstream target of the PI3K/Akt/mTOR signaling route in oral papilloma. These results suggest that Ang-(1-7) may be a novel therapeutic target for OSCC.

Effect of angiotensin II and angiotensin-(1-7) on proliferation of stem cells from human dental apical papilla.

The effects of the renin-angiotensin system (RAS) on stem cells isolated from human dental apical papilla (SCAPs) are completely unknown. Therefore, the aim of this study was to identify RAS components expressed in SCAPs and the effects of angiotensin (Ang) II and Ang-(1-7) on cell proliferation. SCAPs were collected from third molar teeth of adolescents and maintained in cell culture. Messenger RNA expression and protein levels of angiotensin-converting enzyme (ACE), ACE2, and Mas, Ang II type I (AT1) and type II (AT2) receptors were detected in SCAPs. Treatment with either Ang II or Ang-(1-7) increased the proliferation of SCAPs. These effects were inhibited by PD123319, an AT2 antagonist. While Ang II augmented mTOR phosphorylation, Ang-(1-7) induced ERK1/2 phosphorylation. In conclusion, SCAPs produce the main RAS components and both Ang II and Ang-(1-7) treatments induced cell proliferation mediated by AT2 activation through different intracellular mechanisms.

Role of the ACE2/Ang-(1-7)/Mas axis in glucose metabolism.

The renin-angiotensin system (RAS) helps to regulate cardiovascular function, the maintenance of electrolyte and fluid balance, and blood pressure. The RAS contains two axes; the angiotensin-converting enzyme/angiotensin II/Ang II type 1 receptors (ACE/Ang II/AT1) classic axis, which has a role in regulating blood pressure, vascular oxidative stress, coagulation, and cellular proliferation. The other is the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptors (ACE2/Ang-(1-7)/Mas) axis, which can inhibit the former axis, improve fat metabolism, reduce inflammation and oxidative stress, and enhance glucose tolerance and insulin sensitivity. The ACE2/Ang-(1-7)/Mas axis is found in blood vessels, kidneys, liver, pancreas and the brain. It can protect the body from abnormalities in glucose metabolism. The ACE2/Ang-(1-7)/Mas axis can enhance glucose tolerance and improve insulin sensitivity by protecting pancreatic ß cells, increasing insulin secretion, improving glucose metabolism in adipose tissue, enhancing glucose uptake by skeletal muscle, and inhibiting hepatic gluconeogenesis. This article reviews the main characteristics and functions of the ACE2/Ang-(1-7)/Mas axis and its regulation of glucose metabolism in order to demonstrate its potential as a target for the treatment of metabolic diseases such as diabetes.

Angiotensin-(1-7), the product of ACE2 ameliorates NAFLD by acting through its receptor Mas to regulate hepatic mitochondrial function and glycolipid metabolism.

Nonalcoholic fatty liver disease (NAFLD) is the most general liver disease characterized by a continuum of liver abnormalities ranging from simple fatty liver to advanced stage of nonalcoholic steatohepatitis, cirrhosis, and even hepatocellular carcinoma. The pathological drivers of NAFLD are complex and largely undefined. It is increasingly identified that the imbalance between renin-angiotensin system and ACE2/Ang-(1-7)/Mas axis, as well as mitochondrial dysfunction associated with NAFLD. However, no known empirical research has focused on exploring the effect of the regulation of mitochondrial respiration chain activity by Ang-(1-7)/Mas on the prevention of NAFLD. Here, we evaluated the interaction and relevance of hepatic Ang-(1-7)/Mas-axis challenge with glucolipid metabolism and mitochondrial condition in vivo and in vitro. In this context, we found that Mas deletion in mice contributed to the severe glucose intolerance, insulin resistance, and hepatic steatosis which accompanied by elevated levels of serum/ hepatic alanine aminotransferase, aspartate aminotransferase, and triglycerides, as well as the mitochondrial dysfunction. Whereas forced upregulation of Mas or Ang-(1-7) administration could significantly attenuate these consequences by downregulating the expression of hepatic lipogenic proteins and enzymes for gluconeogenesis. Furthermore, activation of Ang-(1-7)/Mas arm could improve the IRS-1/Akt/AMPK pathway and enhance the mitochondrial energy utilization. Considered together, it is becoming extremely hopeful to provide a new perspective for Ang-(1-7)/Mas axis for the therapeutics of NAFLD.

Renin angiotensin aldosterone system in pulmonary fibrosis: Pathogenesis to therapeutic possibilities.

Pulmonary fibrosis is a devastating lung disease with multifactorial etiology characterized by alveolar injury, fibroblast proliferation and excessive deposition of extracellular matrix proteins, which progressively results in respiratory failure and death. Accumulating evidence from experimental and clinical studies supports a central role of the renin angiotensin aldosterone system (RAAS) in the pathogenesis and progression of idiopathic pulmonary fibrosis. Angiotensin II (Ang II), a key vasoactive peptide of the RAAS mediates pro-inflammatory and pro-fibrotic effects on the lungs, adversely affecting organ function. Recent years have witnessed seminal discoveries in the field of RAAS. Identification of new enzymes, peptides and receptors has led to the development of several novel concepts. Of particular interest is the establishment of a protective axis of the RAAS comprising of Angiotensin converting enzyme 2 (ACE2), Angiotensin-(1-7) [Ang-(1-7)], and the Mas receptor (the ACE2/Ang-(1-7)/Mas axis), and the discovery of a functional role for the Angiotensin type 2 (AT2) receptor. Herein, we will review our current understanding of the role of RAAS in lung fibrogenesis, provide evidence on the anti-fibrotic actions of the newly recognized RAAS components (the ACE2/Ang-(1-7)/Mas axis and AT2 receptor), discuss potential strategies and translational efforts to convert this new knowledge into effective therapeutics for PF.