Impact of RAAS Receptors and Membrane-Bound Transporter System in the Left Ventricle during the Long-Term Control of Hypertension.

The Renin-Angiotensin-Aldosterone System (RAAS) has been implicated in systemic and neurogenic hypertension. The infusion of RAAS inhibitors blunted arterial pressure and efficacy of use-dependent synaptic transmission in sympathetic ganglia. The current investigation aims to elucidate the impact of RAAS-mediated receptors on left ventricular cardiomyocytes and the role of the sarcolemma-bound carrier system in the heart of the hypertensive transgene model. A significant increase in mRNA and the protein expression for angiotensin II (AngII) receptor subtype-1 (AT1R) was observed in (mREN2)27 transgenic compared to the normotensive rodents. Concurrently, there was an upregulation in AT1R and a downregulation in the MAS1 proto-oncogene protein receptor as well as the AngII subtype-2 receptor in hypertensive rodents. There were modifications in the expressions of sarcolemma Na+-K+-ATPase, Na+-Ca2+ exchanger, and Sarcoendoplasmic Reticulum Calcium ATPase in the transgenic hypertensive model. These observations suggest chronic RAAS activation led to a shift in receptor balance favoring augmented cardiac contractility and disruption in calcium handling through modifications of membrane-bound carrier proteins and blood pressure. The study provides insight into mechanisms underlying RAAS-mediated cardiac dysfunction and highlights the potential value of targeting the protective arm of AngII in hypertension.

Modulation of ACE2/Ang1-7/Mas and ACE/AngII/AT1 axes affects anticancer properties of sertraline in MCF-7 breast cancer cells.

The renin-angiotensin system (RAS) is best known for playing a major role in maintaining the physiology of the cardiovascular system. Dysregulation of the RAS pathway has been proposed as a link to some malignancies and contributes to cancer metastasis. Breast cancer is considered as one of the leading causes of cancer death in women and its prevention remains yet a challenge. Elements of RAS are expressed in both normal breast tissue and cancerous cells, signifying the essential role of RAS in breast cancer pathology. Sertraline, a widely used antidepressant, has shown anti-proliferative properties on a variety of malignancies. This study aimed to investigate the effect of sertraline and its combination with agonists and antagonists of RAS (A779, Ang 1-7 and losartan) on viability of MCF-7 cells along with their effect on apoptosis and distribution of cell cycle. Our results indicated that sertraline, losartan and Ang 1-7 significantly decreased cell viability, induced apoptosis and cell cycle arrest. A779 blunted the effect of sertraline on cell viability, ROS generation and cell cycle arrest. Combination treatment of sertraline with losartan as well as Ang 1-7 caused a remarkable decline in cell viability. In conclusion, results of the present study support the anti-cancer properties of sertraline, losartan and Ang 1-7 via induction of apoptosis and cell cycle arrest.

The potential role of renin angiotensin system in acute leukemia: a narrative review.

Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.

The Renin-Angiotensin System in Liver Disease.

The renin-angiotensin system (RAS) is a complex homeostatic entity with multiorgan systemic and local effects. Traditionally, RAS works in conjunction with the kidney to control effective arterial circulation, systemic vascular resistance, and electrolyte balance. However, chronic hepatic injury and resulting splanchnic dilation may disrupt this delicate balance. The role of RAS in liver disease, however, is even more extensive, modulating hepatic fibrosis and portal hypertension. Recognition of an alternative RAS pathway in the past few decades has changed our understanding of RAS in liver disease, and the concept of opposing vs. "rebalanced" forces is an ongoing focus of research. Whether RAS inhibition is beneficial in patients with chronic liver disease appears to be context-dependent, but further study is needed to optimize clinical management and reduce organ-specific morbidity and mortality. This review presents the current understanding of RAS in liver disease, acknowledges areas of uncertainty, and describes potential areas of future investigation.

Systematic-Narrative Hybrid Literature Review: Crosstalk between Gastrointestinal Renin-Angiotensin and Dopaminergic Systems in the Regulation of Intestinal Permeability by Tight Junctions.

In the first part of this article, the role of intestinal epithelial tight junctions (TJs), together with gastrointestinal dopaminergic and renin-angiotensin systems, are narratively reviewed to provide sufficient background. In the second part, the current experimental data on the interplay between gastrointestinal (GI) dopaminergic and renin-angiotensin systems in the regulation of intestinal epithelial permeability are reviewed in a systematic manner using the PRISMA methodology. Experimental data confirmed the copresence of DOPA decarboxylase (DDC) and angiotensin converting enzyme 2 (ACE2) in human and rodent enterocytes. The intestinal barrier structure and integrity can be altered by angiotensin (1-7) and dopamine (DA). Both renin-angiotensin and dopaminergic systems influence intestinal Na+/K+-ATPase activity, thus maintaining electrolyte and nutritional homeostasis. The colocalization of B0AT1 and ACE2 indicates the direct role of the renin-angiotensin system in amino acid absorption. Yet, more studies are needed to thoroughly define the structural and functional interaction between TJ-associated proteins and GI renin-angiotensin and dopaminergic systems.

Bibliometric and visual analysis of ACE2/Ang 1-7/MasR axis in diabetes and its microvascular complications from 2000 to 2023.

Background: The pathogenesis of diabetes and its microvascular complications are intimately associated with renin angiotensin system dysregulation. Evidence suggests the angiotensin converting enzyme 2 (ACE2)/angiotensin 1-7 (Ang 1-7)/Mas receptor (MasR) axis regulates metabolic imbalances, inflammatory responses, reduces oxidative stress, and sustains microvascular integrity, thereby strengthening defences against diabetic conditions. This study aims to conduct a comprehensive analysis of the ACE2/Ang 1-7/MasR axis in diabetes and its microvascular complications over the past two decades, focusing on key contributors, research hotspots, and thematic trends. Methods: This cross-sectional bibliometric analysis of 349 English-language publications was performed using HistCite, VOSviewer, CiteSpace, and Bibliometrix R for visualization and metric analysis. Primary analytical metrics included publication count and keyword trend dynamics. Results: The United States, contributing 105 articles, emerged as the most productive country, with the University of Florida leading institutions with 18 publications. Benter IF was the most prolific author with 14 publications, and Clinical Science was the leading journal with 13 articles. A total of 151 of the 527 author's keywords with two or more occurrences clustered into four major clusters: diabetic microvascular pathogenesis, metabolic systems, type 2 diabetes, and coronavirus infections. Keywords such as "SARS", "ACE2", "coronavirus", "receptor" and "infection" displayed the strongest citation bursts. The thematic evolution in this field expanded from focusing on the renin angiotensin system (2002-2009) to incorporating ACE2 and diabetes metabolism (2010-2016). The latter period (2017-2023) witnessed a significant surge in diabetes research, reflecting the impact of COVID-19 and associated conditions such as diabetic retinopathy and cardiomyopathy. Conclusions: This scientometric study offers a detailed analysis of the ACE2/Ang 1-7/MasR axis in diabetes and its microvascular complications, providing valuable insights for future research directions.

Angiotensin (1-7) Inhibits Transforming Growth Factor-Β1-Induced Epithelial-Mesenchymal Transition of Human Keratinocyte Hacat Cells in vitro.

Introduction: Angiotensin (1-7) (Ang-(1-7)) is an emerging component of the renin-angiotensin system (RAS) with effective anti-fibrosis properties and has been shown to interfere with epithelial-mesenchymal transition (EMT) by numerous studies. In recent years, EMT has been proposed as a new therapeutic target for skin fibrotic diseases such as keloids. However, the effect of Ang-(1-7) on EMT in skin is still unclear. Hence, the purpose of this study was to explore the effect of Ang-(1-7) on Transforming growth factor-ß1(TGF-ß1)-induced EMT of human immortalized keratinocytes HaCaT in vitro. Methods: The study involved the use of the human immortalized keratinocyte cell line (HaCaT). The cells were cultured in high-glucose DMEM medium with 10% fetal bovine serum and 1% penicillin-streptomycin. Four groups were created for experimentation: control group (Group C), TGF-ß1-treated group (Group T), Ang-(1-7)-treated group (Group A), and a group treated with both TGF-ß1 and Ang-(1-7) (Group A + T). Various assays were conducted, including a cell proliferation assay using CCK-8 solution, a scratch wound healing assay to evaluate cell migration, and Western blotting to detect protein expressions related to cell characteristics. Additionally, quantitative real-time polymerase chain reaction (PCR) was performed to analyze epithelial-mesenchymal transition (EMT) related gene expression levels. The study aimed to investigate the effects of TGF-ß1 and Ang-(1-7) on HaCaT cells. Results: We found that Ang-(1-7) not only reduced the migration of HaCaT cells induced by TGF-ß1 in vitro but also reduced the expression of α-SMA and vimentin, and restored the protein expression of E-cadherin and claudin-1. Mechanistically, Ang-(1-7) inhibits the phosphorylation levels of Smad2 and Smad3 in the TGF-ß1 canonical pathway, and suppresses the expression of EMT-related transcription factors (EMT-TFs) such as SNAI2, TWIST1, and ZEB1. Discussion: Taken together, our findings suggest that Ang-(1-7) inhibits TGF-ß1-induced EMT in HaCaT cells in vitro by disrupting the TGF-ß1-Smad canonical signaling pathway. These results may be helpful in the treatment of EMT in skin fibrotic diseases such as keloids.

Central angiotensin-(1-7) attenuates hypoglycemia in sepsis-like conditions via reducing systemic and hepatic inflammation.

Sepsis is understood as the result of initiating systemic inflammation derived from an inadequate host response against pathogens. In its acute phase, sepsis is marked by an exacerbated reaction to infection, tissue damage, organ failure, and metabolic dysfunction. Among these, hypoglycemia, characterized by disorders of the gluconeogenesis pathway, is related to one of the leading causes of mortality in septic patients. Recent research has investigated the involvement of sympathetic efferent neuroimmune pathways during systemic inflammation. These pathways can be stimulated by several centrally administered drugs, including Angiotensin-(1-7) (Ang-(1-7)). Therefore, the present study aims to evaluate the effects of central treatment with Ang-(1-7) on hypoglycemia during endotoxemia. For this, male Wistar Hannover rats underwent stereotaxic surgery for intracerebroventricular (i.c.v.) administration of Ang-(1-7) and cannulation of the jugular vein for lipopolysaccharide (LPS) injection. Our results demonstrate that LPS was capable of inducing hypoglycemia and that prior central treatment with Ang-(1-7) attenuated this effect. Our data also show that Ang-(1-7) reduced plasma concentrations of TNF-α, IL-1ß, IL-6, and nitric oxide, in addition to the decrease and increase of hepatic IL-6 and IL-10 respectively, in animals subjected to systemic inflammation by LPS, resulting in the reduction of systemic and hepatic inflammation, thus attenuating the deleterious effects of LPS on phosphoenolpyruvate carboxykinase protein content. In summary, the data suggest that central treatment with Ang-(1-7) attenuates hypoglycemia induced by endotoxemia, probably through anti-inflammatory action, leading to reestablishing hepatic gluconeogenesis.

The role of telomerase reverse transcriptase in the mitochondrial protective functions of Angiotensin-(1-7) in diabetic CD34+ cells.

Angiotensin (Ang)-(1-7) stimulates vasoprotective functions of diabetic (DB) CD34+ hematopoietic stem/progenitor cells partly by decreasing reactive oxygen species (ROS), increasing nitric oxide (NO) levels and decreasing TGFß1 secretion. Telomerase reverse transcriptase (TERT) translocates to mitochondria and regulates ROS generation. Alternative splicing of TERT results in variants α-, ß- and α-ß-TERT, which may oppose functions of full-length (FL) TERT. This study tested if the protective functions of Ang-(1-7) or TGFß1-silencing are mediated by mitoTERT and that diabetes decreases FL-TERT expression by inducing splicing. CD34+ cells were isolated from the peripheral blood mononuclear cells of nondiabetic (ND, n = 68) or DB (n = 74) subjects. NO and mitoROS levels were evaluated by flow cytometry. TERT splice variants and mitoDNA-lesions were characterized by qPCR. TRAP assay was used for telomerase activity. Decoy peptide was used to block mitochondrial translocation (mitoXTERT). TERT inhibitor or mitoXTERT prevented the effects of Ang-(1-7) on NO or mitoROS levels in DB-CD34+ cells. FL-TERT expression and telomerase activity were lower and mitoDNA-lesions were higher in DB cells compared to ND and were reversed by Ang-(1-7) or TGFß1-silencing. The prevalence of TERT splice variants, with predominant ß-TERT expression, was higher and the expression of FL-TERT was lower in DB cells (n = 25) compared to ND (n = 30). Ang-(1-7) or TGFß1-silencing decreased TERT-splicing and increased FL-TERT. Blocking of ß-splicing increased FL-TERT and protected mitoDNA in DB-cells. The findings suggest that diabetes induces TERT-splicing in CD34+ cells and that ß-TERT splice variant largely contributes to the mitoDNA oxidative damage.

Angiotensin-converting enzyme 2 alleviates liver fibrosis through the renin-angiotensin system.

The present letter to the editor is related to the study titled 'Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells'. Angiotensin-converting enzyme 2 can alleviate liver fibrosis by regulating autophagy of hepatic stellate cells and affecting the renin-angiotensin system.

Classical and Alternative Pathways of the Renin-Angiotensin-Aldosterone System in Regulating Blood Pressure in Hypertension and Obese Adolescents.

Primary hypertension (PH) is the leading form of arterial hypertension (AH) in adolescents. Hypertension is most common in obese patients, where 20 to 40% of the population has elevated blood pressure. One of the most effective mechanisms for regulating blood pressure is the renin-angiotensin-aldosterone system (RAAS). The new approach to the RAAS talks about two opposing pathways between which a state of equilibrium develops. One of them is a classical pathway, which is responsible for increasing blood pressure and is represented mainly by the angiotensin II (Ang II) peptide and, to a lesser extent, by angiotensin IV (Ang IV). The alternative pathway is responsible for the decrease in blood pressure and is mainly represented by angiotensin 1-7 (Ang 1-7) and angiotensin 1-9 (Ang 1-9). Our research study aimed to assess changes in angiotensin II, angiotensin IV, angiotensin 1-7, and angiotensin 1-9 concentrations in the plasma of adolescents with hypertension, with hypertension and obesity, and obesity patients. The Ang IV concentration was lower in hypertension + obesity versus control and obesity versus control, respectively p = 0.01 and p = 0.028. The Ang 1-9 concentration was lower in the obesity group compared to the control group (p = 0.036). There were no differences in Ang II and Ang 1-7 peptide concentrations in the hypertension, hypertension and obesity, obesity, and control groups. However, differences were observed in the secondary peptides, Ang IV and Ang 1-9. In both cases, the differences were related to obesity.

Ionizable Lipid Nanoparticle-Mediated TRAIL mRNA Delivery in the Tumor Microenvironment to Inhibit Colon Cancer Progression.

Introduction: Immunotherapy has revolutionized cancer treatment by harnessing the immune system to enhance antitumor responses while minimizing off-target effects. Among the promising cancer-specific therapies, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted significant attention. Methods: Here, we developed an ionizable lipid nanoparticle (LNP) platform to deliver TRAIL mRNA (LNP-TRAIL) directly to the tumor microenvironment (TME) to induce tumor cell death. Our LNP-TRAIL was formulated via microfluidic mixing and the induction of tumor cell death was assessed in vitro. Next, we investigated the ability of LNP-TRAIL to inhibit colon cancer progression in vivo in combination with a TME normalization approach using Losartan (Los) or angiotensin 1-7 (Ang(1-7)) to reduce vascular compression and deposition of extracellular matrix in mice. Results: Our results demonstrated that LNP-TRAIL induced tumor cell death in vitro and effectively inhibited colon cancer progression in vivo, particularly when combined with TME normalization induced by treatment Los or Ang(1-7). In addition, potent tumor cell death as well as enhanced apoptosis and necrosis was found in the tumor tissue of a group treated with LNP-TRAIL combined with TME normalization. Discussion: Together, our data demonstrate the potential of the LNP to deliver TRAIL mRNA to the TME and to induce tumor cell death, especially when combined with TME normalization. Therefore, these findings provide important insights for the development of novel therapeutic strategies for the immunotherapy of solid tumors.

Dysregulation of the renin-angiotensin system in vascular dementia.

The renin-angiotensin system (RAS) regulates systemic and cerebral blood flow and is dysregulated in dementia. The major aim of this study was to determine if RAS signalling is dysregulated in vascular dementia. We measured markers of RAS signalling in white matter underlying the frontal and occipital cortex in neuropathologically confirmed cases of vascular dementia (n = 42), Alzheimer's disease (n = 50), mixed AD/VaD (n = 50) and age-matched controls (n = 50). All cases were stratified according to small vessel disease (SVD) severity across both regions. ACE-1 and ACE-2 protein and activity was measured by ELISA and fluorogenic peptide assays respectively, and angiotensin peptide (Ang-II, Ang-III and Ang-(1-7)) levels were measured by ELISA. ACE-1 protein level and enzyme activity, and Ang-II and Ang-III, were elevated in the white matter in vascular dementia in relation to SVD severity. ACE-1 and Ang-II protein levels were inversely related to MAG:PLP1 ratio, a biochemical marker of brain tissue oxygenation that when reduced indicates cerebral hypoperfusion, in a subset of cases. ACE-2 level was elevated in frontal white matter in vascular dementia. Ang-(1-7) level was elevated across all dementia groups compared to age-matched controls but was not related to SVD severity. RAS signalling was not altered in the white matter in Alzheimer's disease. In the overlying frontal cortex, ACE-1 protein was reduced and ACE-2 protein increased in vascular dementia, whereas angiotensin peptide levels were unchanged. These data indicate that RAS signalling is dysregulated in the white matter in vascular dementia and may contribute to the pathogenesis of small vessel disease.

Angiotensin 1-7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart-The signaling mechanism.

BACKGROUND: The high mortality rate of patients with acute myocardial infarction (AMI) remains the most pressing issue of modern cardiology. Over the past 10 years, there has been no significant reduction in mortality among patients with AMI. It is quite obvious that there is an urgent need to develop fundamentally new drugs for the treatment of AMI. Angiotensin 1-7 has some promise in this regard. OBJECTIVE: The objective of this article is analysis of published data on the cardioprotective properties of angiotensin 1-7. METHODS: PubMed, Scopus, Science Direct, and Google Scholar were used to search articles for this study. RESULTS: Angiotensin 1-7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart. Angiotensin 1-7 can prevent not only ischemic but also reperfusion cardiac injury. The activation of the Mas receptor plays a key role in these effects of angiotensin 1-7. Angiotensin 1-7 alleviates Ca2+ overload of cardiomyocytes and reactive oxygen species production in ischemia/reperfusion (I/R) of the myocardium. It is possible that both effects are involved in angiotensin 1-7-triggered cardiac tolerance to I/R. Furthermore, angiotensin 1-7 inhibits apoptosis of cardiomyocytes and stimulates autophagy of cells. There is also indirect evidence suggesting that angiotensin 1-7 inhibits ferroptosis in cardiomyocytes. Moreover, angiotensin 1-7 possesses anti-inflammatory properties, possibly achieved through NF-kB activity inhibition. Phosphoinositide 3-kinase, Akt, and NO synthase are involved in the infarct-reducing effect of angiotensin 1-7. However, the specific end-effector of the cardioprotective impact of angiotensin 1-7 remains unknown. CONCLUSION: The molecular nature of the end-effector of the infarct-limiting effect of angiotensin 1-7 has not been elucidated. Perhaps, this end-effector is the sarcolemmal KATP channel or the mitochondrial KATP channel.

Novel Insights into the Cardioprotective Effects of the Peptides of the Counter-Regulatory Renin-Angiotensin System.

Currently, cardiovascular diseases are a major contributor to morbidity and mortality worldwide, having a significant negative impact on both the economy and public health. The renin-angiotensin system contributes to a high spectrum of cardiovascular disorders and is essential for maintaining normal cardiovascular homeostasis. Overactivation of the classical renin-angiotensin system is one of the most important pathophysiological mechanisms in the progression of cardiovascular diseases. The counter-regulatory renin-angiotensin system is an alternate pathway which favors the synthesis of different peptides, including Angiotensin-(1-7), Angiotensin-(1-9), and Alamandine. These peptides, via the angiotensin type 2 receptor (AT2R), MasR, and MrgD, initiate multiple downstream signaling pathways that culminate in the activation of various cardioprotective mechanisms, such as decreased cardiac fibrosis, decreased myocardial hypertrophy, vasodilation, decreased blood pressure, natriuresis, and nitric oxide synthesis. These cardioprotective effects position them as therapeutic alternatives for reducing the progression of cardiovascular diseases. This review aims to show the latest findings on the cardioprotective effects of the main peptides of the counter-regulatory renin-angiotensin system.

ACE2 Regulates Glycolipid Metabolism in Multiple Tissues.

Angiotensin-converting enzyme 2 (ACE2) is a member of the renin-angiotensin system (RAS), which was once considered a linear cascade. ACE2 mainly functions to convert AngiotensinⅡ (AngⅡ) to Angiotensin1-7 (A1-7). The biologically active product A1-7 then binds to the Mas receptor to form the ACE2/A1-7/Mas axis. In contrast to classic RAS, which plays a decisive role in regulation, the ACE2/A1-7/Mas axis effectively counteracts vasoconstriction, the inflammatory response, oxidative stress, and cell proliferation, and is thus a negative regulator of the RAS. ACE2 also functions as a chaperone to regulate intestinal amino acid uptake. It is widely expressed in the lungs, cardiovascular system, gastrointestinal tract, kidney, pancreas and adipose tissue. Previous studies have confirmed that ACE2 has a vital role in homeostasis. ACE2 also has a variety of other biological activities and plays a critical role in Type 2 diabetes (T2DM) and its complications, especially diabetic nephropathy, obesity, dyslipidemia and other diseases. In this review, we summarize the latest research on the regulation of glucose and lipid metabolism by ACE2 in different organs. Our focus was particularly on T2DM, with the aim of providing new clinical ideas for the use of ACE2 as an effective target in the prevention and treatment of metabolic diseases.

The antihypertensive action of C-phycocyanin is related to the prevention of angiotensin II-caused vascular dysfunction in chronic kidney disease.

C-phycocyanin (CPC) is a photosynthetic protein found in Arthrospira maxima with a nephroprotective and antihypertensive activity that can prevent the development of hemodynamic alterations caused by chronic kidney disease (CKD). However, the complete nutraceutical activities are still unknown. This study aims to determine if the antihypertensive effect of CPC is associated with preventing the impairment of hemodynamic variables through delaying vascular dysfunction. Twenty-four normotensive male Wistar rats were divided into four groups: (1) sham + 4 mL/kg/d vehicle (100 mM of phosphate buffer, PBS) administered by oral gavage (og), (2) sham + 100 mg/kg/d og of CPC, (3) CKD induced by 5/6 nephrectomy (CKD) + vehicle, (4) CKD + CPC. One week after surgery, the CPC treatment began and was administrated daily for four weeks. At the end treatment, animals were euthanized, and their thoracic aorta was used to determine the vascular function and expression of AT1, AT2, and Mas receptors. CKD-induced systemic arterial hypertension (SAH) and vascular dysfunction by reducing the vasorelaxant response of angiotensin 1-7 and increasing the contractile response to angiotensin II. Also, CKD increased the expression of the AT1 and AT2 receptors and reduced the Mas receptor expression. Remarkably, the treatment with CPC prevented SAH, renal function impairment, and vascular dysfunction in the angiotensin system. In conclusion, the antihypertensive activity of CPC is associated with avoiding changes in the expression of AT1, AT2, and Mas receptors, preventing vascular dysfunction development and SAH in rats with CKD.

The Counteracting Effects of Ang II and Ang-(1-7) on the Function and Growth of Insulin-secreting NIT-1 Cells.

INTRODUCTION: China now has the highest number of diabetes in the world. Angiotensin II (Ang II) causes insulin resistance by acting on the insulin signaling pathway of peripheral target tissues. However, its effect on islet ß-cells remains unclear. The possible role of Angiotensin-(1-7) [Ang-(1-7)] as an antagonist to the effects of Ang II and in treating diabetes needs to be elucidated. OBJECTIVES: To assess the effects of Ang II and Ang-(1-7) on the function and growth of islet ß cell line NIT-1, which is derived from the islets of non-obese diabetic/large T-antigen (NOD/LT) mice with insulinoma. METHODS: NIT-1 cells were treated with Ang II, Ang-(1-7) and their respective receptor antagonists. The impact on cell function and growth was then evaluated. RESULTS: Ang II significantly reduced insulin-stimulated IR-ß-Tyr and Akt-Ser; while Ang-(1-7), saralasin (an Ang II receptor antagonist), and diphenyleneiodonium [DPI, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) antagonist] reversed the inhibiting effect. Conversely, Ang II significantly increased insulin-stimulated intracellular H2O2 and P47 phox, while saralasin and DPI reverted the effect. Furthermore, Ang-(1-7) reduced the elevated concentrations of ROS and MDA while increasing the proliferation rate that was reduced by high glucose, all of which were reversed by A-779, an antagonist of the Mas receptor (MasR). CONCLUSION: Angiotensin II poses a negative regulatory effect on insulin signal transduction, increases oxidative stress, and may inhibit the transcription of insulin genes stimulated by insulin in NIT-1 cells. Meanwhile, angiotensin-(1-7) blocked these effects via MasR. These results corroborate the rising potential of the renin-angiotensin system (RAS) in treating diabetes.

Targeting PI3K/p-Akt/eNOS, Nrf2/HO-1, and NF-κB/p53 signaling pathways by angiotensin 1-7 protects against liver injury induced by ischemia-reperfusion in rats.

The liver is an important organ, and hepatic ischemia-reperfusion (IR) injury is a frequent pathophysiological process that can cause significant morbidity and mortality. Thus, our study aimed to investigate the effect of targeting PI3K/p-Akt/eNOS (phosphoinositide 3-kinase/phospho-protein kinase B/endothelial nitric oxide synthase), Nrf2/HO-1 (nuclear factor-erythroid 2-related factor-2/heme oxygenase-1), and NF-κB/p53 (nuclear factor-κB/tumor protein 53) signaling pathways by using angiotensin (1-7) [ang-(1-7)] against hepatic injury induced by IR. Thirty-two male rats were included in sham group, ang-(1-7)-treated group, hepatic IR group, and hepatic IR group treated with ang-(1-7). The levels of hepatic ang-(1-7), angiotensin II (Ang II), angiotensin-converting enzyme 2 (ACE2), HO-1, malondialdehyde (MDA), PI3K, and p-Akt were assessed. The expressions of eNOS and B-cell leukemia/lymphoma-2 (BCL-2) in the liver were determined. Histological assessment and immunohistochemical expression of NF-κB, p53, and Nrf2 were carried out. The levels of reduced glutathione (GSH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in serum were estimated. Results showed that administration of ang-(1-7) to hepatic IR rats led to significant amelioration of hepatic damage through a histological evaluation that was associated with significant upregulation of the expressions of PI3K/p-Akt/eNOS and Nrf2/HO-1 with downregulation of NF-κB/p53 signaling pathways. In conclusion, PI3K/p-Akt/eNOS and Nrf2/HO-1 signaling pathways are involved in the protective effects of ang-(1-7) against hepatic damage induced by IR. Therefore, ang-(1-7) can be used to prevent hepatic IR, which occurs in certain conditions such as liver transplantation, hemorrhagic shock, and severe infection.

Effects of oral HPΒCD-angiotensin-(1-7) supplementation on recreational mountain bike athletes: a crossover study.

BACKGROUND: Supplementation with Angiotensin-(1-7) [(Ang-1-7)] has received considerable attention due to its possible ergogenic effects on physical performance. The effects of a single dose of Ang-(1-7) on the performance of mountain bike (MTB) athletes during progressive load tests performed until the onset of voluntary fatigue have previously been demonstrated. This study tested the effects of Ang-(1-7) in two different exercise protocols with different metabolic demands: aerobic (time trial) and anaerobic (repeated sprint). METHODS: Twenty one male recreational athletes were given capsules containing an oral formulation of HPßCD-Ang-(1-7) (0.8 mg) and HPßCD-placebo (only HPßCD) over a 7-day interval; a double-blind randomized crossover design was used. Physical performance was examined using two protocols: a 20-km cycling time trial or 4 × 30-s repeated all-out sprints on a leg cycle ergometer. Data were collected before and after physical tests to assess fatigue parameters, and included lactate levels, and muscle activation during the sprint protocol as evaluated by electromyography (EMG); cardiovascular parameters: diastolic and systolic blood pressure and heart rate; and performance parameters, time to complete (time trial), maximum power and mean power (repeated sprint). RESULTS: Supplementation with an oral formulation of HPßCD-Ang-(1-7) reduced basal plasma lactate levels and promoted the maintenance of plasma glucose levels after repeated sprints. Supplementation with HPßCD-Ang-(1-7) also increased baseline plasma nitrite levels and reduced resting diastolic blood pressure in a time trial protocol. HPßCD-Ang-(1-7) had no effect on the time trial or repeat sprint performance, or on the EMG recordings of the vastus lateralis and vastus medialis. CONCLUSIONS: Supplementation with HPßCD-Ang-(1-7) did not improve physical performance in time trial or in repeated sprints; however, it promoted the maintenance of plasma glucose and lactate levels after the sprint protocol and at rest, respectively. In addition, HPßCD-Ang-(1-7) also increased resting plasma nitrite levels and reduced diastolic blood pressure in the time trial protocol. TRIAL REGISTRATION: RBR-2nbmpbc, registered January 6th, 2023. The study was prospectively registered.