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Aim. To assess the relationship between arterial stiffness and renin-angiotensin system (RAS) gene polymorphism in patients with COronaVIrus Disease 2019 (COVID-19).Material and methods: 100 patients (mean age of 58.1±11.98 years; 51% women, 49% men) were included in the cross-ectional study. This study included adult patients with laboratory-confirmed diagnosis of COVID-19 admitted to the University Hospital. All patients were evaluated for arterial stiffness using cardio-ankle vascular index (CAVI) by sphygmomanometry. Also alleles and genotypes of several polymorphic markers were identified by real-time polymerase chain reaction in human DNA preparations: rs4762 of angiotensinogen (AGT) gene, rs1799752 of angiotensin-converting enzyme type 1 gene (ACE1), rs5186 of angiotensin II type 1 receptor gene (ATP1), and rs1403543 of angiotensin II type 2 receptor gene (ATP2). The distributions of alleles and genotypes in groups with normal and elevated arterial stiffness (CAVI ≥9.5) were compared.Results. Elevated arterial stiffness (CAVI ≥9.5) was found in 29%. A significantly higher frequency of ATP1 rs5186 genotypes including the A allele, i.e., A/A+A/C versus C/C, was found in subjects with normal CAVI: 95.0% and 5.0% compared with 87.5% and 12.5% in those with CAVI ≥9.5 (χ2=3.907, p=0.049). A significantly higher frequency of genotypes involving the D allele (DD and ID) was detected in patients with increased stiffness: 95.0% compared to 81.3% in the group with normal stiffness (χ2=9.280, p

To maintain healthy human physiology and promote growth and development, it is imperative to consume milk, which provides essential nutrients like vitamins and minerals. However, cow milk compounds contain different types of molecules, which may elicit varied responses within individuals. Milk metabolites are studied to impact several human biological processes that result in altered physiology. The Renin-Angiotensin System (RAS) is responsible for regulating blood pressure and maintaining a proper balance of fluids and electrolytes. However, impaired regulation of RAS may cause medical conditions such as heart failure, kidney disease, or hypertension. RAS is one of the studied systems, whose proteins reportedly interacted with and were affected by milk metabolites. The study attempts to find milk metabolites with high affinity towards RAS-proteins, and results from circumstances of interaction between them. Molecular docking between milk metabolites and RAS-proteins' and an interaction network was utilized to achieve the objective. In total 206 milk metabolites and 13 Ras proteins are considered for the study. Network analysis depends on the docking score, which helps us understand the interaction between milk molecules. Based on free energy analysis study indicates that out of 206, 35 milk metabolites showed free energy < -8 Kcal/mol, which indicates high binding affinity between these metabolites with 12 RAS-proteins. Four RAS proteins, i.e., ANPEP, CTSA, MRGPRD, and ACE, were found to have significantly interacted with more than 15 milk metabolites. Based on binding affinity, we can predict whether the specific metabolites with effective binding scores modulate the function of specific RAS proteins.

Ascites is the most common complication in patients with decompensated cirrhosis. This condition results in a severely impaired quality of life, excessive healthcare use, recurrent hospitalizations and significant morbidity and mortality. While loop diuretics and mineralocorticoid receptor antagonists are commonly employed for symptom relief, our understanding of their impact on survival remains limited. A comprehensive understanding of the underlying pathophysiological mechanism of ascites is crucial for its optimal management. The renin-angiotensin-aldosterone system (RAAS) is increasingly believed to play a pivotal role in the formation of cirrhotic ascites, as RAAS overactivation leads to a reduction in urine sodium excretion then a decrease in the ability of the kidneys to excrete water. In this review, the authors provide an overview of the pathogenesis of cirrhotic ascites, the challenges associated with current pharmacologic treatments, and the previous attempts to modulate the RAAS, followed by a description of some emerging targeted RAAS agents with the potential to be used to treat ascites.

Abstract Background The exact pathogenesis of Huntington’s disease (HD) remains unclear. However, mitochondrial dysfunction and oxidative stress are supposed to play a significant role. The objective of this study was to examine the possible neuroprotective effect of Lisinopril (Lisino) in a 3-nitropropionic acid-produced HD in rats. Methods Sixty-four rats were divided into four groups (16/group): Group (1): Normal control group, Group (2): Lisinopril control group, Group (3): 3-NP non-treated group, and Group (4): (3-NP + Lisinopril) group. Behavior assessments (open field test, rotarod test, grip strength test) were performed along with different histological and biochemical parameters. Results Lisinopril upregulated the expression of the ACE2/Ang1-7/MAS receptor (MasR) axis of RAS, which triggered the PI3K/Akt pathway and prompted the CREB/BDNF neurogenesis signal. Furthermore, Lisinopril remarkably downregulated the inflammatory cytokines (NF-κB, TNF-α, IFN-γ and IL-6), decreased apoptotic markers (p53, BAX/Bcl2 ratio, Cyt-c and caspase-3) and upgraded the mitochondrial TFAM content and SDH activity along with restoration of the redox mechanism by recovering SOD, catalase, GSH and Nrf2. Conclusion Notably, the outcomes of this study disclosed that Lisinopril could be a future neuroprotective therapeutic candidate against HD.

Abstract Background Age-related reproductive aging is a natural and irreversible physiological process, and delaying childbearing is increasingly common all over the world. Transplantation of mesenchymal stem cells (MSCs) is considered a new and effective therapy to restore ovarian function, but the relevant mechanisms remain unclear. Recently, it has been found that there is a local Renin–angiotensin system (RAS) in human ovary and it plays a key role. Methods After collecting follicular fluid from women who received oocyte retrieval for pure male factor infertility, the level of RAS components in it were detected, and the correlation analysis by linear regression. Then, the in vivo experiments on female C57BL/6 mice were designed to measure ovarian function, and the transcription and translation levels of RAS pathway were detected by molecular biology methods. Moreover, the role of RAS in regulating inflammation and oxidative stress in the co-culture system were explored in in vitro experiments on KGN cells. Results First, a total of 139 samples of analyzable follicular fluid were obtained. The local RAS of ovary, which is independent of systemic RAS (P > 0.05), is affected by age (Pearson r 0.05). Conclusions Together, our findings indicate that a novel possible mechanism to explain how stem cells restore age-related ovarian functional decline.

Objective To investigate the changes of angiotensin-converting enzyme （ACE） and angiotensin-converting enzyme 2 （ACE2） levels in children with severe Mycoplasma pneumoniae pneumonia （SMPP） and evaluates their clinical values in predicting the severity of SMPP. Methods A total of 71 children with Mycoplasma pneumoniae pneumonia （MPP group） and 63 with severe Mycoplasma pneumoniae pneumonia （SMPP group） admitted to the Second Hospital of Lanzhou University from October 2020 to December 2023 were recruited in this study. Additionally， 20 healthy children undergoing routine health check-ups during this period were selected as the control group. The serum concentrations of ACE and ACE2 in the three groups were measured using the enzyme-linked immunosorbent assay （ELISA）， and laboratory test results were collected for comparison and correlation analysis between the MPP and SMPP groups. The receiver operating characteristic （ROC） curve was delineated to assess the predictive values of one single index or combined for SMPP. Results In the three groups， the serum ACE level was the highest in the SMPP group and the lowest in the healthy control group. The serum ACE2 level was the highest in the MPP group and the lowest in the healthy control group （all P < 0.008）. Compared to the MPP group， the SMPP group exhibited significantly elevated white blood cell count （WBC）， neutrophil percentage （NE%）， C-reactive protein （CRP）， serum amyloid A protein （SAA）， procalcitonin （PCT）， interleukin-6 （IL-6）， erythrocyte sedimentation rate （ESR）， and D-dimer （all P < 0.001） and these indexes were positively correlated with ACE levels （all P < 0.05）， but negatively correlated with ACE2 levels （all P < 0.05）. The lymphocyte percentage （LY%） was significantly reduced （P < 0.001）， which was positively correlated with ACE2 levels （P < 0.05）， whereas negatively correlated with ACE levels （P < 0.05）. Lactate dehydrogenase （LDH） was elevated （P < 0.05）， which was negatively correlated with ACE2 levels （P < 0.05）， but not correlated with ACE levels （P > 0.05）. The monocyte percentage （MO%） showed neither significant difference nor correlation （both P > 0.05）. ROC curve analysis revealed that ACE， ACE2， CRP， D-dimer， LDH， and combined detection of ACE+ACE2， CRP+D-dimer+LDH all had predictive values for SMPP. Among them， the combined detection of ACE+ACE2 showed the highest predictive value， with an AUC of 0.991 and 95% CI： 0.981-1.000. Conclusion The levels of ACE and ACE2 are likely associated with the onset and progression of SMPP in children， and both ACE and ACE2 serve as good indicators for predicting SMPP.

Rationale & Objective: Blood pressure (BP) control is essential for preventing cardiorenal complications in chronic kidney disease (CKD), but most patients fail to reach BP target. We assessed longitudinal patterns of antihypertensive drug prescription and systolic BP. Study Design: Prospective observational cohort study. Setting & Population: In total, 2,755 hypertensive patients with CKD stages 3-4, receiving care from a nephrologist, from the French CKD–Renal Epidemiology and Information Network (CKD-REIN cohort study). Exposure: Patient factors, including sociodemographic characteristics, medical history, and laboratory data, and provider factors, including number of primary care physician and specialist encounters. Outcomes: Changes in antihypertensive drug-class prescription during follow-up: add-on or withdrawal. Analytical Approach: Hierarchical shared-frailty models to estimate hazard ratios (HR) to deal with clustering at the nephrologist level and linear mixed models to describe systolic BP trajectory. Results: At baseline, median age was 69 years, and mean estimated glomerular filtration rate was 33 mL/min/1.73 m². In total, 66% of patients were men, 81% had BP ≥ 130/80 mm Hg, and 75% were prescribed ≥2 antihypertensive drugs. During a median 5-year follow-up, the rate of changes of antihypertensive prescription was 50 per 100 person-years, 23 per 100 for add-ons, and 25 per 100 for withdrawals. After adjusting for risk factors, systolic BP, and the number of antihypertensive drugs, poor medication adherence was associated with increased HR for add-on (1.35, 95% confidence interval [CI], 1.01-1.80), whereas a lower education level was associated with increased HR for withdrawal (1.23, 95% CI, 1.02-1.49) for 9-11 years versus ≥12 years. More frequent nephrologist visits (≥4 vs none) were associated with higher HRs of add-on and withdrawal (1.52, 95% CI, 1.06-2.18; 1.57, 95% CI, 1.12-2.19, respectively), whereas associations with visit frequency to other physicians varied with their specialty. Mean systolic BP decreased by 4 mm Hg following drug add-on but tended to increase thereafter. Limitations: Lack of information on prescriber and drug dosing. Conclusions: In patients with CKD and poor BP control, changes in antihypertensive drug prescriptions are common and relate to clinician preferences and patients’ tolerability. Sustainable reduction in systolic BP after add-on of a drug class is infrequently achieved. Plain-Language Summary: Blood pressure (BP) control remains unattained in most patients with chronic kidney disease (CKD), raising questions about how antihypertensive treatment is managed. Our study highlights dynamic, yet heterogeneous patterns of antihypertensive drug prescriptions in patients with CKD stages 3-4 receiving care from a nephrologist over 5 years of follow-up. Modifiable factors such as high body mass index and poor medication adherence were associated with higher hazard of adding-on an antihypertensive drug class, independently of baseline BP and antihypertensive treatment. Similarly, lower education level was associated with antihypertensive drug withdrawn, as was more frequent visits to primary care physicians, underlining the importance of coordinated care. Sustainable reduction in systolic BP after add-on of a drug class is infrequently achieved and may be related to drug withdrawal and poor treatment adherence.

Angiotensin I converting enzyme (ACE1) maintains blood pressure homeostasis by converting angiotensin I into angiotensin II in the renin-angiotensin system (RAS). ACE1 is expressed in the brain, where an intrinsic RAS regulates complex cognitive functions including learning and memory. ACE1 has been implicated in neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, but the mechanisms remain incompletely understood. Here, we performed single-nucleus RNA sequencing to characterize the expression of RAS genes in the hippocampus and discovered that Ace is mostly expressed in CA1 region excitatory neurons. To gain a deeper understanding of the function of neuronal ACE1, we generated ACE1 conditional knockout (cKO) mice lacking ACE1 expression specifically in hippocampal and cortical excitatory neurons. ACE1 cKO mice exhibited hippocampus-dependent memory impairment in the Morris water maze, y-maze, and fear conditioning tests. Total ACE1 level was significantly reduced in the cortex and hippocampus of ACE1 cKO mice showing that excitatory neurons are the predominant cell type expressing ACE1 in the forebrain. Despite similar reductions in total ACE1 level in both the hippocampus and cortex, the RAS pathway was dysregulated in the hippocampus only. Importantly, ACE1 cKO mice exhibited age-related capillary loss selectively in the hippocampus. Here, we show selective vulnerability of the hippocampal microvasculature and RAS pathway to neuronal ACE1 knockout. Our results provide important insights into the function of ACE1 in the brain and demonstrate a connection between neuronal ACE1 and cerebrovascular function in the hippocampus.

This study aimed to screen peptides with antihypertensive effects from the α-chymotrypsin hydrolysate of Sebastes schlegelii (SSA). SSA demonstrated ACE inhibitory activity with an IC50 value of 0.062 ± 0.001 mg/mL. The SSA significantly reduced body weight and systolic blood pressure in the SHR spontaneously hypertensive rat (SHR) model and improved hypertension-induced vasopathy and interstitial fibrosis in heart and vascular tissues, indicating the presence of ACE inhibitory peptides contributing to cardiovascular health. Peptide composition analysis identified fractions of SSA with potent ACE inhibitory activity, particularly those with molecular weights of 5 kDa or less. Further evaluation of ACE activity using Sephadex G-10 separated SSA fractions led to the amino acid sequence analysis of the most effective fraction (SSA-F1). Molecular docking simulations predicted that peptides from SSA-F1 inhibit ACE activity by binding to its active sites. This research suggests the potential of peptides from S. schlegelii for clinical hypertension treatment.

Patients with chronic kidney disease (CKD) bear a significant financial burden and face numerous complications and higher mortality rates. The progression of CKD is associated with glomerular injury caused by glomerular hyperfiltration and oxidative stress. Factors such as uncontrolled hypertension, elevated urine protein levels, anemia, and underlying glomerular disease, contribute to CKD progression. In addition to conservative treatment, several medications are available to combat the progression of CKD to end-stage kidney disease. Renin-angiotensin-aldosterone system blockers could slow the progression of CKD by reducing glomerular hyperfiltration, lowering blood pressure, and decreasing inflammation. Mineralocorticoid receptor antagonists inhibit the mineralocorticoid receptor signaling pathway, thereby attenuating inflammation and fibrosis. Sodium-glucose cotransporter 2 inhibitors exhibit protective effects on the kidneys and against cardiovascular events. Tolvaptan, a selective vasopressin V2-receptor antagonist, decelerates the rate of increase in total kidney volume and deterioration of kidney function in patients with rapidly progressive autosomal dominant polycystic kidney disease. The protective effects of AST-120 remain controversial. Due to a lack of evidence regarding the efficacy and safety of these medications in children, it is imperative to weigh the benefits and adverse effects carefully. Further research is essential to establish the efficacy and safety profiles in pediatric populations.

Abstract Background Dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme released into the bloodstream after tissue injury, that can degrade angiotensin II. High concentrations of circulating DPP3 (cDPP3) have been associated with worse outcomes during sepsis. The aim of this study was to assess the effect of Procizumab (PCZ), a monoclonal antibody that neutralizes cDPP3, in an experimental model of septic shock. Methods In this randomized, open-label, controlled study, 16 anesthetized and mechanically ventilated pigs with peritonitis were randomized to receive PCZ or standard treatment when the mean arterial pressure (MAP) dropped below 50 mmHg. Resuscitation with fluids, antimicrobial therapy, peritoneal lavage, and norepinephrine was initiated one hour later to maintain MAP between 65–75 mmHg for 12 h. Hemodynamic variables, tissue oxygenation indices, and measures of organ failure and myocardial injury were collected. Organ blood flow was assessed using isotopic assessment (99mtechnetium albumin). cDPP3 activity, equilibrium analysis of the renin–angiotensin system and circulating catecholamines were measured. Tissue mRNA expression of interleukin-6 and downregulation of adrenergic and angiotensin receptors were assessed on vascular and myocardial samples. Results PCZ-treated animals had reduced cDPP3 levels and required less norepinephrine and fluid than septic control animals for similar organ perfusion and regional blood flow. PCZ-treated animals had less myocardial injury, and higher PaO2/FiO2 ratios. PCZ was associated with lower circulating catecholamine levels; higher circulating angiotensin II and higher angiotensin II receptor type 1 myocardial protein expression, and with lower myocardial and radial artery mRNA interleukin-6 expression. Conclusions In an experimental model of septic shock, PCZ administration was associated with reduced fluid and catecholamine requirements, less myocardial injury and cardiovascular inflammation, along with preserved angiotensin II signaling. Graphical Abstract

Abstract Aims Regulation of the renin‐angiotensin system (RAS) in heart failure (HF) with reduced ejection fraction (HFrEF) still raises questions, as a large proportion of patients show normal renin levels despite manifest disease. Experimental venous congestion results in reduced renal perfusion pressure and stimulates renin secretion. We hypothesized that excess renin levels are mainly a result of right ventricular failure as a sequalae of left ventricular dysfunction. The study aimed to link right ventricular function (RVF) with renin levels and to investigate further contributors to excess RAS activation. Methods and results Three hundred thirty‐two chronic HFrEF patients undergoing routine ambulatory care were consecutively enrolled in a prospective, registry‐based, observational study. Laboratory parameters, including cardiac‐specific markers renin, aldosterone, and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), echocardiographic examination (n = 247), and right heart catheterization (n = 85), were documented. The relationship between renin and its respective parameters was analysed. Renin concentration was not associated with the New York Heart Association class or NT‐proBNP. Systolic blood pressure, systemic vascular resistance, serum sodium, aldosterone, and lactate dehydrogenase were associated with increased renin levels (P

Previous studies on renin-angiotensin-aldosterone system (RAAS) mainly focus on renin, prorenin and prorenin receptor (PRR), which play an important role in cardiovascular, renal and other diseases. The physiological function of PRR has been widely studied. Soluble prorenin receptor (sPRR) is generated by cleavage of extracellular components of PRR by protease and secreted into extracellular space, therefore the change of sPRR level may reflect the change of RAAS in tissue. However, there are limited clinical researchs on sPRR. In recent years, increasing evidences show that sPRR has important biological functions in various pathophysiological processes. This article summarized the recent advances in sPRR in cardiovascular system, kidney diseases, respiratory diseases, endocrine and metabolic diseases, pregnancy complications and cancers, and considered that sPRR may be a new biomarker of multiple diseases, and has potential therapeutic effects on metabolic diseases.

Objective(s): Pulmonary arterial hypertension (PAH) is a severe and often fatal disease that is associated with oxidative stress and inflammation. Alamandine, a component of the renin-angiotensin system, known for its antioxidative, anti-inflammatory, and antifibrotic effects, has been investigated in this study to determine if it has protective effects against PAH induced by monocrotaline (MCT) and if these effects are associated with oxidative stress, inflammatory factors, and inducible nitric oxide synthase (iNOS).Materials and Methods: Rats were administered MCT (40 mg/kg) on day 0 and then received alamandine (50 mg/kg/day) via mini-osmotic pumps for 21 days starting one day later. Hemodynamic parameters, electrocardiograms, superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), inflammatory cytokines (TNF-α, IL-1β, and NF-κB), iNOS, and MrgD receptor expression in lung tissue were evaluated at the end of the 21-day period. The MrgD receptor was quantified through immunofluorescent staining, and the histopathology of lung tissues was evaluated using hematoxylin and eosin staining. Results: The results showed that alamandine treatment significantly improved hemodynamic parameters, oxidative stress markers, inflammatory factors, and electrocardiographic data. Furthermore, treatment with alamandine decreased the levels of iNOS. Additionally, alamandine treatment decreased the expression levels of MrgD receptors in the lung tissue of MCT-induced PAH. Conclusion: In summary, this study indicates that alamandine has protective effects against monocrotaline-induced PAH, and these effects may be attributed to the inhibition of oxidative stress, inflammatory parameters, and iNOS.

Muscle atrophy due to limb immobilization and inactivity is a common consequence of many diseases and treatment processes. One of the systems activated in inflammatory conditions is the renin-angiotensin system (RAS). The present study was conducted with the aim of investigating the effects of one of the angiotensin-converting enzyme (ACE) inhibitors, enalapril, on improving muscle atrophy caused by immobility. The study was conducted in three groups: a control, an atrophy, and an atrophy group treated with enalapril on Balb/c mice. After tying a splint to cause atrophy in one of the legs, daily treatment with enalapril intraperitoneally (dissolved in DMSO) at a dose of 10 mg/kg/day was done for 7 days. On the eighth day, the splint was opened and half of the mice were evaluated. Then, in the recovery phase, treatment with enalapril was continued in the remaining mice for 10 days without a splint. At the end of each phase, the mice were examined for the muscle strength of the lower limb muscles, and histological and biochemical analyses were subsequently carried out. The tissue level of the oxidative stress index MDA was evaluated, which showed a significantly lower level in the enalapril group compared to the atrophy group (*P

Abstract Aortic aneurysm (AA) is an aortic disease with a high mortality rate, and other than surgery no effective preventive or therapeutic treatment have been developed. The renin–angiotensin system (RAS) is an important endocrine system that regulates vascular health. The ACE2/Ang‐(1–7)/MasR axis can antagonize the adverse effects of the activation of the ACE/Ang II/AT1R axis on vascular dysfunction, atherosclerosis, and the development of aneurysms, thus providing an important therapeutic target for the prevention and treatment of AA. However, products targeting the Ang‐(1–7)/MasR pathway still lack clinical validation. This review will outline the epidemiology of AA, including thoracic, abdominal, and thoracoabdominal AA, as well as current diagnostic and treatment strategies. Due to the highest incidence and most extensive research on abdominal AA (AAA), we will focus on AAA to explain the role of the RAS in its development, the protective function of Ang‐(1–7)/MasR, and the mechanisms involved. We will also describe the roles of agonists and antagonists, suggest improvements in engineering and drug delivery, and provide evidence for Ang‐(1–7)/MasR's clinical potential, discussing risks and solutions for clinical use. This study will enhance our understanding of AA and offer new possibilities and promising targets for therapeutic intervention.

Background: Oryeongsan (Wulingsan, Goreisan) has long been used for the treatment of impaired body fluid metabolism. However, the action mechanisms have not been clearly defined. Recently, effects of Oryeongsan on the body fluid and Na+ metabolism and the action mechanisms have been shown more clearly. The present review focuses on the recent findings on the effects of Oryeongsan in the cardio-renal system in relation with body fluid metabolism and action mechanisms leading to a decrease in blood pressure in animal models of hypertension. Methods: The new and recent findings were searched by using searching systems including PubMed-NCBI and Google-Scholar. Results: Oryeongsan induced an increase in glomerular filtration rate, and natriuresis and diuresis with a decreased osmolality and resulted in a contraction of the body fluid and Na+ balance. These findings were associated with a suppression of abundance of Na+-H+-exchanger isoform 3 expression and V2 receptor/aquaporin2 water channel signaling pathway in the kidney. Further, treatment with Oryeongsan accentuated atrial natriuretic peptide secretion in the atria from spontaneously hypertensive rats in which the secretion was suppressed. In addition, Oryeongsan ameliorated impaired vasodilation in spontaneously hypertensive rats. Conclusion: The effects of Oryeongsan in the kidney, atria, and vessel were accompanied by a suppression of AT1 receptor and concurrent accentuation of abundance of AT2/Mas receptors expression and modulation of the natriuretic peptide system in these organs from hypertensive rats. The review shows multiple sites of action of Oryeongsan and mechanisms involved in the regulation of volume and pressure homeostasis in the body.

Perivascular adipose tissue (PVAT) regulates vascular tonus with an anticontractile effect, which may be dysfunctional in hypertension. An Egg White Hydrolysate (EWH), a bioactive food, restores endothelium dysfunction and reduces blood pressure levels in malignant hypertension. We aimed to evaluate whether dietary supplementation with EWH interferes with the PVAT function in the mesenteric resistance arteries (MRA) of DOCA-salt hypertensive animals and the mechanisms involved. Male rats were divided into 4 groups and treated for 8 weeks. For 4 weeks, DOCA-salt or vehicle-treated rats (SHAM) were induced, and after that, some rats were co-treated with DOCA-salt or vehicle plus EWH (1 g/kg/day) for 4 weeks more. MRA and/or their PVAT (mPVAT) were used for functional, molecular, and biochemical analysis. The anticontractile effect of mPVAT in response to norepinephrine (NE) was observed only in MRA rings with PVAT of the SHAM group, while this effect was abolished in DOCA-salt rings. The EWH treatment did not change the anticontractile effect of mPVAT in SHAM but partially restored it in DOCA-salt rats. Acute aliskiren incubation reduced NE-induced contraction only in MRA with PVAT of DOCA-salt rats. EWH prevented the overactivation of the renin levels and ACE activity in mPVAT of DOCA-salt rats; while did not change AT1R expression, but increased AT2R expression. In mPVAT, EWH blocked the increase of MDA, ROS and pro-inflammatory cytokines observed in DOCA-salt rats. EWH improved PVAT dysfunction in MRA of severe hypertension. This beneficial effect could be mediated by an ameliorated redox balance, inflammatory state, and RAS axis.

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.

Abstract Background Pregnancy is characterized by profound circulatory changes and compensatory adjustments in the renin-angiotensin-aldosterone system (RAAS). Differences in regulatory response may antedate or accompany vascular complicated pregnancy. We performed a systematic review and meta-analysis to delineate the trajectory of active plasma renin concentration (APRC) in healthy pregnancy and compare this to complicated pregnancy. Methods We performed a systematic review and meta-analysis on APRC during normotensive and hypertensive pregnancies, using PubMed (NCBI) and Embase (Ovid) databases. We included only studies reporting measurements during pregnancy together with a nonpregnant reference group measurement. Risk of bias was assessed with QUIPS. Ratio of the mean (ROM) and 95% confidence intervals (CI) of APRC values between pregnant and nonpregnant women were estimated for predefined intervals of gestational age using a random-effects model. Meta-regression was used to analyze APRC over time. Results In total, we included 18 studies. As compared to nonpregnant, APRC significantly increased as early as the first weeks of healthy pregnancy and stayed increased throughout the whole pregnancy (ROM 2.77; 95% CI 2.26–3.39). APRC in hypertensive complicated pregnancy was not significantly different from nonpregnancy (ROM 1.32; 95% CI 0.97–1.80). Conclusion Healthy pregnancy is accompanied by a profound rise in APRC in the first trimester that is maintained until term. In hypertensive complicated pregnancy, this increase in APRC is not observed.

The (pro)renin receptor ((P)RR) is an essential component of the renin–angiotensin system (RAS) as a specific single-pass transmembrane receptor for prorenin and renin and has now emerged as a multifunctional protein implicated in a wide variety of developmental and physio-pathological processes and pathways. The (P)RR may be of pathological significance in metabolic syndrome. The (P)RR has received much consideration; substantial efforts have been made to understand the localization, regulation, and function of the (P)RR at both a molecular and system level. (P)RR regulation of cell function depends on whether it is intact or cleaved into its constituent forms. Therefore, the present chapter describes immunohistochemical approaches to examine the expression of (P)RR in various organs. It was shown that different molecular forms of (P)RR could be present in different tissue compartments in almost all organs. Among them, the liver has high PRR activity. Our findings could elucidate more detailed distribution of different (P)RR molecular forms in different organs, which could provide useful information to further investigate the pathophysiological mechanisms of the development of various diseases in the future.

Abstract The etiology of polycystic ovary syndrome (PCOS) is complex and variable, and there is no exact cause or good treatment method. Most of the methods of hormones are used to temporarily meet the needs of patients. Experimental evidence has shown that trehalose has, anti-apoptotic, anti-oxidative, glucose-lowering, and insulin resistance effects. However, whether trehalose has a therapeutic effect on PCOS is unknown. It has been reported that the ovarian renin-angiotensin system (OVRAS) is involved in the development of PCOS, but it has not been fully elucidated. This study aims to explore the effect of trehalose on PCOS and elucidate the related OVRAS mechanism. We first observed that body weight, estrous cycle, ovarian follicles at all levels, glucose tolerance, serum hormones, and insulin resistance were improved by trehalose treatment in the PCOS mouse model. Moreover, trehalose treatment also ameliorated ovarian oxidative stress and apoptosis in PCOS mice, as determined by TUNNEL apoptosis staining, total SOD in ovarian homogenate, and WB assay. OVRAS mainly involves two classic pathways, namely the ACE/AngII/AT1R/AT2R, and ACE2 / Ang1-7/ MASR, Which play different functions. In PCOS mouse ovaries, we found that ACE/AngII/AT1R was up-regulated and ACE2/Ang1-7/MASR and AT2R were down-regulated by PCR and WB experiments, However, trehalose treatment changed its direction. In addition, we also found that trehalose ameliorated DHEA-induced oxidative stress and apoptosis in KGN by PCR and WB experiments, mainly by down-regulating ACE/AngII/AT1R. Our study shows that trehalose improves symptoms of PCOS mainly by down-regulating ACE/AngII/AT1R, revealing a potential therapeutic target for PCOS.

Abstract Obesity over‐activates the classical arm of the renin‐angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin‐converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high‐fat (HF) diet for 16 weeks. At the eighth week, the HF‐fed animals were divided into four subgroups—sedentary (HF), treated with enalapril (HF‐E), exercise training protocol (HF‐T), and combined interventions (HF‐ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF‐T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity‐induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training.

The purpose of the review is to evaluate the interaction of angiotensin-converting enzyme inhibitors in patients with glaucoma and concomitant arterial hypertension using literature data. Glaucoma is the main cause of blindness and visual impairment, as well as the main cause of irreversible blindness worldwide. Pharmacotherapy, laser or surgical treatments are used to reduce IOP levels, as well as prevent deterioration of visual field defects. However, 40 % of patients develop glaucomatous neuropathy despite ongoing therapy. This prompts the investigation of alternative causes of damage to the optic nerve, and abnormal blood pressure levels, both too low and too high, are considered as a possible risk factor. Arterial hypertension occurs in 48–65 % of patients with glaucoma and is the most common systemic disease in patients with glaucoma. Currently, angiotensin converting enzyme (ACE) inhibitors are considered the “gold standard” in the treatment of arterial hypertension, in the pathogenesis of which activation of the renin-angiotensin system (RAS) plays an important role. The renin-angiotensin system (RAS) is a hormonal system responsible for regulating blood pressure and fluid and electrolyte balance in the body. Local tissue-specific RAS were found, including in the structures of the eyeball: cornea, aqueous humor, iris, ciliary body, vitreous body, retina. These data indicate that the local RAS plays an important role in the regulation of the physiology of the eye and may become a target in the development of new antiglaucoma drugs. Animal studies, as well as studies in various patient groups, show that systemic antihypertensive drugs that inhibit the RAS, such as ACE inhibitors, reduce IOP. These studies support the concept that RAS inhibitory drugs may be potential antiglaucoma drugs in the future, as ACE inhibitors can improve the outflow of intraocular fluid, thereby reducing IOP.

A large number of studies have shown that severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) can cause potential harm to cerebral small blood vessels and may further lead to nervous system injury. With reference to related cases, this article analyzes the different types of cerebral small vessel disease (CSVD) secondary to coronavirus disease 2019 and the mechanism of SARS-CoV-2 inducing CSVD, in order to provide new ideas for the pathogenesis and prevention of CSVD and a theoretical basis for regular cranial imaging examinations for patients infected with SARS-CoV-2.

Abstract Background The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS. Methods Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO2/FiO2-ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality. Results Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2–161.5], p = 0.0028). Similarly, oxygenation index decreased by − 6.0 cmH2O/mmHg at hour-48 with angiotensin-II versus − 0.4 cmH2O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH2O/mmHg, [95%CI − 8.6 to − 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5–47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group. Conclusions In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock. Trial Registration: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

Atrial fibrillation (AF) is a common cardiac arrhythmia that often occurs in patients with structural heart disease and is a significant cause of morbidity and mortality in clinical settings. AF is typically associated with significant changes of both the structure of the atria and the cardiac conduction system. AF can result in reduced heart function, heart failure, and various other complications. Current drug therapy for AF patients is often ineffective and may have adverse effects. Radiofrequency ablation is more effective than traditional drug therapy, but this invasive procedure carries potential risks and may lead to postoperative recurrence, limiting the clinical benefits to some extent. Therefore, in-depth research into the molecular mechanisms of AF and exploration of new treatment strategies based on research findings are prerequisites for improving the treatment of AF and the associated cardiac conditions. Long noncoding RNAs (lncRNAs) are a new class of noncoding RNA (ncRNAs) with a length exceeding 200 nt, which regulate gene expression at multiple levels. Increasing evidence suggests that lncRNAs participate in many pathological processes of AF initiation, development, and maintenance, such as structural remodeling, electrical remodeling, renin-angiotensin system anomalies, and intracellular calcium deregulation s. LncRNAs that play key roles in structural and electrical remodeling may become molecular markers and targets for AF diagnosis and treatment, respectively, while lncRNAs critical to autonomic nervous system remodeling may bring new insights into the prognosis and recurrence of AF. This review article provides a synopsis on the up-to-date research findings relevant to the roles of lncRNAs in AF.

Abstract Alport syndrome is a rare genetic disease that results in disordered basement membrane type IV collagen resulting in haematuria, proteinuria and often development of renal fibrosis leading to progressive kidney disease. The therapeutic blockage of the renin-angiotensin-aldosterone system, which slows the progression to kidney failure, is supported by strong evidence. Recent clinical trials using sodium-glucose co-transporter-2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRA) in patients with chronic kidney disease have changed the therapeutic landscape. Patients with Alport syndrome and progressive kidney disease may benefit from treatment with MRAs because research has shown that these drugs are nephroprotective through a variety of mechanisms, including by preventing fibrosis. Ongoing clinical trials show great promise in order to help establish the long-term safety and efficacy of Finerenone, a MRA. This review discusses the evidence for the use of MRAs as a potential treatment in Alport syndrome that may slow the progression of chronic kidney disease and prevent patients reaching kidney failure.

Abstract Background Vitamin D, one of the most essential micronutrients, is crucial in various health outcomes. However, previous studies showed conflicting results and uncertainty about vitamin D supplementation's optimal dosage and duration. In this study, we aimed to evaluate the vitamin D supplements efficiency on serum levels of 25-hydroxy vitamin D (25(OH)D), 1,25-dihdroxy vitamin D (1,25(OH)2D), parathyroid hormone (PTH) and renin–angiotensin–aldosterone system (RAAS) in adults. Methods A systematic analysis of eligible and relevant randomized-controlled trials (RCT) published before April 2023 assessing the effect of vitamin D supplementations applied. The studies were identified by searching several databases, including Pubmed, Scopus, Web of Science, ProQuest, and Cochrane Register of controlled trials. Results Five eligible RCTs with 346 participants in the intervention and 352 participants in the control group were assessed in our project. According to the results, there was a substantial change in 25(OH)D (SMD: 2.2, I 2 : 92.3, 95% Confidence Interval (CI): 1.38–3.02, P-value: 0.048) and 1,25(OH)2D (SMD:1.23, I 2 : 86.3, 95% CI: 0.01- 2.44, P-value

Abstract Background Renin–angiotensin system and its ACE2/Ang(1-7)/Mas receptor axis regulates skeletal response to multiple physiological and pathological conditions. Recent research suggested a vital role of Ang(1-7) in regulating alveolar bone metabolism and remodeling. In this context, this study evaluated the effects of the Ang(1-7)/Mas receptor axis on orthodontic tooth movement (OTM) and the alveolar bone response to mechanical load. Methods A coil spring was placed between the right maxillary first molar and the anterior tooth of Wistar rats to apply bidirectional mechanical force. Ang(1-7) with or without a specific Mas receptor antagonist (A779) was infused using subcutaneous osmotic pumps (200 and 400 ng/kg/min: respectively). Animals were killed after 5 and 14 days from the OTM procedure after the clinical evaluation of tooth movement and mobility. Morphometric analysis of alveolar bone structure was conducted using micro-CT and the histological picture was evaluated after H&E staining. Moreover, collagen fiber distribution was assessed using Picro-Sirius red stain. In addition, bone samples were collected from the pressure and tension sites around the anterior tooth for gene expression analysis. Results Ang(1-7) infusion suppressed the tooth movement and mobility after 14 days of the orthodontic force application. Additionally, Ang(1-7) infusion preserved the morphometric and histological structure of the alveolar bone at pressure and tension sides. These effects were abolished by adding A779 infusion. Collagen fiber distribution was dysregulated mainly by the A779 Mas receptor blockage. Ang(1-7) affected the bone formation, remodeling- and vascularity-related genes in the pressure and tension sides, suggesting a prominent suppression of osteoclastogenesis. Ang(1-7) also improved osteoblasts-related genes on the tension side, whereas the osteoclasts-related genes were augmented by A779 on the pressure side. Conclusion Collectively, the activation of Ang(1-7)/Mas receptor axis appears to hinder tooth movement and regulates alveolar bone remodeling in response to mechanical force. Graphical abstract

Neurological diseases, including neurodegenerative diseases (NDDs), are the primary cause of disability worldwide and the second leading cause of death. The chronic nature of these conditions and the lack of disease-modifying therapies highlight the urgent need for developing effective therapies. To accomplish this, effective models of NDDs are required to increase our understanding of underlying pathophysiology and for evaluating treatment efficacy. Traditionally, models of NDDs have focused on the central nervous system (CNS). However, evidence points to a relationship between systemic factors and the development of NDDs. Cardiovascular disease and related risk factors have been shown to modify the cerebral vasculature and the risk of developing Alzheimer’s disease. These findings, combined with reports of changes to vascular density and blood–brain barrier integrity in other NDDs, such as Huntington’s disease and Parkinson’s disease, suggest that cardiovascular health may be predictive of brain function. To evaluate this, we explore evidence for disruptions to the circulatory system in murine models of NDDs, evidence of disruptions to the CNS in cardiovascular disease models and summarize models combining cardiovascular disruption with models of NDDs. In this study, we aim to increase our understanding of cardiovascular disease and neurodegeneration interactions across multiple disease states and evaluate the utility of combining model systems.

Non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is alarmingly increasing alongside the cases of obesity worldwide. MASLD is an underestimated metabolic abnormality closely linked with a higher risk of developing systemic arterial hypertension (SAH). However, the underlying mechanism of association between MASLD and SAH remains unknown. Inflammation may link these two entities by regulating the renin-angiotensin system (RAS). For this reason, in this study, we evaluated the hepatic expression of a cytokine profile and critical molecules in the RAS pathway in patients with morbid obesity and MASLD, both with SAH. We found a statistically significant correlation between ACE levels and the cytokines IL-4, IL-10, and IL-13 of Th2 response. Furthermore, according to a multiple linear regression analysis, the cytokines IL-4 and IL-13 were the best predictors of ACE levels. Moreover, we observed increased hepatic IL-13 expression in patients with morbid obesity, MASLD, and SAH compared to those without SAH. These results allow us to propose, for the first time, that the Th2 response, through regulating the RAS, could play a critical role in developing SAH in individuals with MASLD and obesity.

Background: Mesenchymal stem cell (MSC) transplantation is a promising therapy for kidney repair. This study compared the regenerative effects of feline MSCs (fMSCs) and telmisartan, a renin-angiotensin blocker (RAB), in a feline model of chronic kidney disease (CKD). Methods: The fMSCs were obtained from 35 Persian cats with CKD and characterized by CD44, CD90, and CD105 markers by using real-time RT-qPCR. The cats were randomly allocated to four groups, fMSCs injection (first group), telmisartan administration (second group), no treatment (third group), and healthy controls (fourth group). The study was conducted in Kerman province from December 2018 to December 2019. The factors that may affect the risk of CKD, such as age, weight, and history of kidney diseases, were considered as independent variables. The presence or absence of CKD was the dependent variable. The cats were followed up for 120 days and evaluated by physical examination, glomerular filtration rate (GFR), blood urea nitrogen (BUN), serum creatinine (SCr), serum urea, alanine transaminase (ALT), urine specific gravity (SG), and kidney histopathology. Statistical analysis was performed using SPSS software (version 20) with two-way ANOVA and Tukey test. P

Purpose: to determine the role of the systemic angiotensin II (AT-II) in the pathogenesis of retinopathy of prematurity (ROP) and assess its prognostic value.Material and methods. 34 premature infants at risk of developing ROP were examined according to the ophthalmological ROP screening protocol adopted in the Russian Federation. Retrospectively, the infants were divided into 2 groups: those without ROP (n = 15) and those with developed ROP (n = 19). The average gestational age of those without ROP was 28.12 ± 0.64 weeks, their average body weight at birth was 1164 ± 118.6 g. The respective values for the group with ROP were 27.8 ± 0.6 weeks and 1142.6 ± 108.4 g. The two groups had similar extent of general somatic burden. At 32–35 weeks and 36–39 weeks of post-conceptual age (PCA), the infants of both groups were tested for the concentration of AT-II in blood serum using the enzyme-linked immunosorbent assay (ELISA).Results: on the 32–35 week of PCA, the average level of AT-II in blood serum of premature infants of the ROP group was significantly increased as compared to that of the non-ROP group (p = 0.03), while on the 36–39 week of PCA no statistically significant difference between the AT-II levels in the examined groups was found (p = 0.73).Conclusion. We established that the systemic AT-II level has a trigger role in the development of ROP. A high level of this parameter found at the onset of ROP can be considered as an early prognostic criterion for the risk of ROP development.

Diabetic nephropathy (DN) represents a significant microvascular complication in diabetes, entailing intricate molecular pathways and mechanisms associated with cardiorenal vascular diseases. Prolonged hyperglycemia induces renal endothelial dysfunction and damage via metabolic abnormalities, inflammation, and oxidative stress, thereby compromising hemodynamics. Concurrently, fibrotic and sclerotic alterations exacerbate glomerular and tubular injuries. At a macro level, reciprocal communication between the renal microvasculature and systemic circulation establishes a pernicious cycle propelling disease progression. The current management approach emphasizes rigorous control of glycemic levels and blood pressure, with renin-angiotensin system blockade conferring renoprotection. Novel antidiabetic agents exhibit renoprotective effects, potentially mediated through endothelial modulation. Nonetheless, emerging therapies present novel avenues for enhancing patient outcomes and alleviating the disease burden. A precision-based approach, coupled with a comprehensive strategy addressing global vascular risk, will be pivotal in mitigating the cardiorenal burden associated with diabetes.

Abstract Mechanisms underlying hyperoxia‐induced airflow restriction in the pediatric lung disease Bronchopulmonary dysplasia (BPD) are unclear. We hypothesized a role for Renin‐Angiotensin System (RAS) activity in BPD. RAS is comprised of a pro‐developmental pathway consisting of angiotensin converting enzyme‐2 (ACE2) and angiotensin II receptor type 2 (AT2), and a pro‐fibrotic pathway mediated by angiotensin II receptor type 1 (AT1). We investigated associations between neonatal hyperoxia, airflow restriction, and RAS activity in a BPD mouse model. C57 mouse pups were randomized to normoxic (FiO2 = 0.21) or hyperoxic (FiO2 = 0.75) conditions for 15 days (P1–P15). At P15, P20, and P30, we measured airflow restriction using plethysmography and ACE2, AT1, and AT2 mRNA and protein expression via polymerase chain reaction and Western Blot. Hyperoxia increased airflow restriction P15 and P20, decreased ACE2 and AT2 mRNA, decreased AT2 protein, and increased AT1 protein expression. ACE2 mRNA and protein remained suppressed at P20. By P30, airflow restriction and RAS expression did not differ between groups. Hyperoxia caused high airflow restriction, increased pulmonary expression of the pro‐fibrotic RAS pathway, and decreased expression of the pro‐developmental in our BPD mouse model. These associated findings may point to a causal role for RAS in hyperoxia‐induced airflow restriction.

Background We have previously reported that male mice exposed to maternal separation and early weaning (MSEW), a model of early life stress, show sympathetic activation and increased blood pressure in response to a chronic high‐fat diet. The goal of this study was to investigate the contribution of the renin–angiotensin–aldosterone system to the mechanism by which MSEW increases blood pressure and vasomotor sympathetic tone in obese male mice. Methods and Results Mice were exposed to MSEW during postnatal life. Undisturbed litters served as controls. At weaning, both control and MSEW offspring were placed on a low‐fat diet or a high‐fat diet for 20 weeks. Angiotensin peptides in serum were similar in control and MSEW mice regardless of the diet. However, a high‐fat diet induced a similar increase in angiotensinogen levels in serum, renal cortex, liver, and fat in both control and MSEW mice. No evidence of renin–angiotensin system activation was found in adipose tissue and renal cortex. After chronic treatment with enalapril (2.5 mg/kg per day, drinking water, 7 days), an angiotensin‐converting enzyme inhibitor that does not cross the blood–brain barrier, induced a similar reduction in blood pressure in both groups, while the vasomotor sympathetic tone remained increased in obese MSEW mice. In addition, acute boluses of angiotensin II (1, 10, 50 μg/kg s.c.) exerted a similar pressor response in MSEW and control mice before and after enalapril treatment. Conclusions Overall, elevated blood pressure and vasomotor sympathetic tone remained exacerbated in MSEW mice compared with controls after the peripheral inhibition of angiotensin‐converting enzyme, suggesting a mechanism independent of angiotensin II.

Abstract Aims Large outcome studies demonstrated a reduction of heart failure hospitalization or cardiovascular death in patients with chronic heart failure (CHF). The renin–angiotensin system (RAS) is a key player in fluid and sodium regulation. The classic angiotensin‐converting enzyme–angiotensin II–angiotensin‐1 receptor axis (Ang I–ACE–Ang II receptor axis) is predominantly angiotensin II (Ang‐II) induced and promotes vasoconstriction. In contrast, the angiotensin‐converting‐enzyme‐2–angiotensin‐(1‐7)–Mas axis (Mas‐axis) is mediated by the metabolites angiotensin‐1‐7 (Ang‐(1‐7)) and angtiotensin‐1‐5 (Ang‐(1‐5)) and exerts cardioprotective effects. Methods We previously investigated the effect of empagliflozin on the systemic haemodynamic in patients with stable CHF (NYHA II–III) in a randomized placebo‐controlled clinical trial ‘Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure (ELSI)’. In a post hoc analysis, we now analysed whether empagliflozin has an effect on the RAS by measuring detailed RAS profiles (LC‐MS/MS‐based approach) in 72 patients from ELSI. We compared RAS parameters after 1‐month and 3‐months treatment with empagliflozin or placebo to baseline. The secondary goal was to analyse whether the effect of empagliflozin on RAS parameters was dependent on angiotensin‐receptor‐blocking (ARB) or angiotensin‐converting‐enzyme‐inhibitor (ACEI) co‐medication. Results Empagliflozin medication induced a significant rise in Ang‐II [68.5 pmol/L (21.3–324.2) vs. 131.5 pmol/L (34.9–564.0), P = 0.001], angiotensin‐I (Ang‐I) [78.7 pmol/L (21.5–236.6) vs. 125.9 pmol/L (52.6–512.9), P

Abstract Background Assisted reproductive technology (ART) is associated with an increased risk of adverse metabolic health in offspring, and these findings have been demonstrated in animal models without parental infertility issues. However, it is unclear what changes lead to abnormal metabolism. The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. Thus, we focused on the local RAS of the liver, which is the central organ for glucose and lipid metabolism in offspring conceived by in vitro fertilization (IVF), and studied the role of local liver RAS in metabolic diseases. Methods Male C57BL/6 mouse offspring obtained by natural pregnancy and IVF were fed a standard chow diet or a high-fat diet (HFD) from 4 weeks of age through 16 weeks of age. We assessed glucose and lipid metabolism, hepatic histopathology, and the gene and protein expression of key RAS components. In addition, the blocker losartan was used from 4 weeks of age through 16 weeks of age to investigate the regulatory mechanisms of abnormal local RAS on metabolic activity in the IVF offspring liver. Results The growth trajectories of IVF offspring body and liver weights were different from those of naturally pregnant offspring. Impaired glucose tolerance (IGT) and insulin resistance (IR) occurred in IVF-conceived male offspring. After continuous HFD feeding, male offspring in the IVF group underwent earlier and more severe IR. Furthermore, there was a trend of lipid accumulation in the livers of chow-fed IVF offspring. Hepatic steatosis was also more serious in the IVF offspring after HFD treatment. Type 1 receptor (AT1R), which is the primary receptor mediating the action of angiotensin (Ang) II, has been confirmed to be upregulated in IVF offspring livers. Losartan reduced or even eliminated most of the significant differences between the IVF and NC groups after HFD consumption. Conclusions The upregulation of AT1R expression in the liver increased the activity of the local RAS, resulting in abnormal glucose and lipid metabolism and lipid accumulation in the liver, significantly increasing the risk of nonalcoholic fatty liver disease (NAFLD) in IVF offspring.

Preeclampsia is an obstetric pathology with striking similarities to COVID-19. The renin-angiotensin system plays a key role in the pathogenesis of both diseases. This report reviews the pharmacological strategies that have been suggested for the prevention and treatment of preeclampsia and that are potentially useful also in the treatment of COVID-19. Of note, both pathologies have in common an Angiotensin II-mediated endothelial dysfunction secondary to an angiogenic imbalance, with effects on vasculature, coagulation, and inflammation. These considerations are drawn from cases of the initial SARS-CoV-2 primary infection and may not apply to more recent SARS-CoV-2 variants or infections after COVID vaccination. The treatment options discussed included albumin infusion, aspirin, corticosteroids, the monoclonal antibody eculizumab, hydroxychloroquine, low molecular weight heparin, magnesium, melatonin, metformin, nitric oxide, proton pump inhibitors, statins, therapeutic apheresis, and vitamin D.

The renin–angiotensin system (RAS) is increasingly being recognized to play a role in the tumor microenvironment, promoting tumor growth. Studies blocking a single part of the RAS have shown mixed results, possibly due to the existence of different bypass pathways and redundancy within the RAS. As such, multimodal blockade of the RAS has been developed to exert more complete inhibition of the RAS. The aim of the present study was to assess the safety of multimodal RAS blockade in dogs. Five dogs (four with appendicular osteosarcoma, one with oral malignant melanoma) were treated with atenolol, benazepril, curcumin, meloxicam, and metformin. The dogs underwent clinical examination, blood pressure measurement, and hematology and serum biochemistry tests performed at 0, 1, 3, 6, 9, and 12 weeks, then every 3 months thereafter. End-of-life decisions were made by the owners. None of the dogs developed hypotension. One dog had intermittent vomiting during the 64 weeks it was on the trial. One dog had a one-off increase in serum SDMA(symmetrical dimethylarginine) concentration. Dogs were euthanized at weeks 3 (osteosarcoma), 10 (osteosarcoma), 17 (osteosarcoma), and 26 (oral malignant melanoma), and one dog was still alive at the end of the trial at 64 weeks (osteosarcoma). This is the first assessment of multimodal blockade of the RAS in dogs, and the results suggest it causes only mild adverse effects in some animals. The efficacy of the treatment was not assessed due to the small number of dogs. This pilot study allows for future larger studies assessing multimodal RAS blockade for the treatment of canine cancer.

Prolylcarboxypeptidase (PRCP, PCP, Lysosomal Pro-X-carboxypeptidase, Angiotensinase C) controls angiotensin- and kinin-induced cell signaling. Elevation of PRCP appears to be activated in chronic inflammatory diseases [cardiovascular disease (CVD), diabetes] in proportion to severity. Vascular endothelial cell senescence and mitochondrial dysfunction have consistently been shown in models of CVD in aging. Cellular senescence, a driver of age-related dysfunction, can differentially alter the expression of lysosomal enzymes due to lysosomal membrane permeability. There is a lack of data demonstrating the effect of age-related dysfunction on the expression and function of PRCP. To explore the changes in PRCP, the PRCP-dependent prekallikrein (PK) pathway was characterized in early- and late-passage human pulmonary artery endothelial cells (HPAECs). Detailed kinetic analysis of cells treated with high molecular weight kininogen (HK), a precursor of bradykinin (BK), and PK revealed a mechanism by which senescent HPAECs activate the generation of kallikrein upon the assembly of the HK–PK complex on HPAECs in parallel with an upregulation of PRCP and endothelial nitric oxide (NO) synthase (eNOS) and NO formation. The NO production and expression of both PRCP and eNOS increased in early-passage HPAECs and decreased in late-passage HPAECs. Low activity of PRCP in late-passage HPAECs was associated with rapid decreased telomerase reverse transcriptase mRNA levels. We also found that, with an increase in the passage number of HPAECs, reduced PRCP altered the respiration rate. These results indicated that aging dysregulates PRCP protein expression, and further studies will shed light into the complexity of the PRCP-dependent signaling pathway in aging.

Background Endoplasmic reticulum (ER) stress has been shown to play a critical role in the pathogenesis of hypertension. However, the underlying mechanisms for lowering blood pressure (BP) by suppressing ER stress remain unclear. Here, we hypothesized that inhibition of ER stress could restore the balance between RAS components and lower BP in spontaneously hypertensive rats (SHRs). Methods Wistar-Kyoto (WKY) rats and SHRs received vehicle or 4-PBA, an ER stress inhibitor, in the drinking water for 4 weeks. BP was measured by tail-cuff plethysmography, and the expression of RAS components was examined by Western blot. Results Compared with vehicle-treated WKY rats, vehicle-treated SHRs exhibited higher blood pressure and increased renal ER stress and oxidative stress, accompanied by impaired diuresis and natriuresis. Moreover, SHRs had higher ACE and AT1R and lower AT2R, ACE2, and MasR expressions in the kidney. Interestingly, 4-PBA treatment improved impaired diuresis and natriuresis and lowered blood pressure in SHRs, accompanied by reducing ACE and AT1R protein expression and increasing AT2R, ACE2, and MasR expression in the kidneys of SHRs. In addition, these changes were associated with the reduction of ER stress and oxidative stress. Conclusions These results suggest that the imbalance of renal RAS components was associated with increased ER stress in SHRs. Inhibition of ER stress with 4-PBA reversed the imbalance of renal RAS components and restored the impaired diuresis and natriuresis, which, at least in part, explains the blood pressure-lowering effects of 4-PBA in hypertension.

ABSTRACTThe renin-angiotensin system (RAS) operates within adipose tissue. Obesity-related changes can affect adipose RAS, predisposing to hypertension, type 2 diabetes, and possibly severe COVID-19. We evaluated the in vitro research on human adipose RAS and identified gaps in the literature. Medline (Ovid), Embase (Ovid), Web of Science, Scopus, and 1findr were searched to identify relevant studies. Fifty primary studies met our inclusion criteria for analysis. Expression of RAS components (n = 14), role in differentiation (n = 14), association with inflammation (n = 15) or blood pressure (n = 7) were investigated. We found (1) obesity-related changes in RAS were frequently studied (30%); (2) an upswing of articles investigating adipose ACE-2 expression since the COVID-19 pandemic; (3) a paucity of papers on AT2R and Ang (1–7)/MasR which counterbalance Ang II/ART1; (4) weight loss lowered adipose ACE-2 mRNA expression; and (5) angiotensin receptor blockers (ARBs) reduced deleterious effects of angiotensin II. Overall, these studies link Ang II/ATR1 signalling to impaired adipogenesis and a pro-inflammatory dysfunctional adipose tissue, with ATR1 blockade limiting these responses. ACE-2 may mitigate Ang II effects by converting it to Ang(1–7) which binds MasR. More work is needed to understand adipose RAS in various pathologic states such as obesity and COVID-19 infection.T.

The renin-angiotensin system (RAS) is a central modulator of cardiovascular physiology. Pathophysiology of hypertension is commonly accompanied by hyper-activation of RAS. Angiotensin II receptor blockers (ARBs) and Angiotensin-converting enzyme (ACE) inhibitors are the gold standard treatment for hypertension. Recently, several studies highlighted the crucial role of immune system in hypertension. Angiotensin-II-induced hypertension is associated with low grade inflammation characterized by innate and adaptive immune system dysfunction. Throughout the progression of hypertension, monocyte/macrophage cells appear to have a crucial role in vascular inflammation and interaction with the arterial wall. Since myelomonocytic cells potentially play a key role in angiotensin-II-induced hypertension and organ damage, pharmacological targeting of RAS components in monocyte/macrophages may possibly present an innovative strategy for treatment of hypertension and related pathology.

Abstract Background Hypertensive emergency is a critical disease that causes multifaceted sequelae, including end-stage kidney disease and cardiovascular disease. Although the renin–angiotensin–aldosterone (RAA) system is enormously activated in this disease, there are few reports that attempt to characterize the effect of early use of RAA inhibitors (RASi) on the temporal course of kidney function. Methods This retrospective cohort study was conducted to clarify whether the early use of RASi during hospitalization offered more favorable benefits on short-term renal function and long-term renal outcomes in patients with hypertensive emergencies. We enrolled a total of 49 patients who visited our medical center with acute severe hypertension and multiple organ dysfunction between April 2012 and August 2020. Upon admission, the patients were treated with intravenous followed by oral antihypertensive drugs, including RASi and Ca channel blockers (CCB). Kidney function as well as other laboratory and clinical parameters were compared between RASi-treated and CCB- treated group over 2 years. Results Antihypertensive treatment effectively reduced blood pressure from 222 ± 28/142 ± 21 to 141 ± 18/87 ± 14 mmHg at 2 weeks and eGFR was gradually restored from 33.2 ± 23.3 to 40.4 ± 22.5 mL/min/1.73m2 at 1 year. The renal effect of antihypertensive drugs was particularly conspicuous when RASi was started in combination with other conventional antihypertensive drugs at the early period of hospitalization (2nd day [IQR: 1–5.5]) and even in patients with moderately to severely diminished eGFR (

Abstract 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 PaO2/FiO2 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.

Objective To investigate the effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on renal function and renin-angiotensin-aldosterone system (RAAS) in elderly patients with early diabetic kidney disease (DKD). Methods A total of 97 elderly patients with type 2 diabetes mellitus (T2DM) who attended our hospital from September 1, 2019 to August 1, 2021 were enrolled, and according to urinary albumin-to-creatinine ratio (UACR), they were divided into normal UACR group and early DKD group. A random number table was further used to determine whether each patient in the above two groups was treated with dapagliflozin. Finally, all patients were divided into normal-UACR dapagliflozin group (group A), normal-UACR control group (group B), early-DKD dapagliflozin group (group C), and early-DKD control group (group D), and these four groups were compared in terms of the changes in related clinical indices at 1 year after treatment. Results After 1 year of treatment, group A had significant changes in body mass index (BMI), systolic blood pressure, diastolic blood pressure, UACR, annualized relapse rate (ARR), fasting blood glucose, and fasting insulin (t=2.098-7.122,P

Abstract Background Cellular entry of SARS-CoV-2 has been shown to rely on angiotensin-converting enzyme 2 (ACE2) receptors, whose expression in the testis is among the highest in the body. Additionally, the risk of mortality seems higher among male COVID-19 patients, and though much has been published since the first cases of COVID-19, there remain unanswered questions regarding SARS-CoV-2 impact on testes and potential consequences for reproductive health. We investigated testicular alterations in non-vaccinated deceased COVID-19-patients, the precise location of the virus, its replicative activity, and the immune, vascular, and molecular fluctuations involved in the pathogenesis. Results We found that SARS-CoV-2 testicular tropism is higher than previously thought and that reliable viral detection in the testis requires sensitive nanosensors or RT-qPCR using a specific methodology. Through an in vitro experiment exposing VERO cells to testicular macerates, we observed viral content in all samples, and the subgenomic RNA’s presence reinforced the replicative activity of SARS-CoV-2 in testes of the severe COVID-19 patients. The cellular structures and viral particles, observed by transmission electron microscopy, indicated that macrophages and spermatogonial cells are the main SARS-CoV-2 lodging sites, where new virions form inside the endoplasmic reticulum Golgi intermediate complex. Moreover, we showed infiltrative infected monocytes migrating into the testicular parenchyma. SARS-CoV-2 maintains its replicative and infective abilities long after the patient’s infection. Further, we demonstrated high levels of angiotensin II and activated immune cells in the testes of deceased patients. The infected testes show thickening of the tunica propria, germ cell apoptosis, Sertoli cell barrier loss, evident hemorrhage, angiogenesis, Leydig cell inhibition, inflammation, and fibrosis. Conclusions Our findings indicate that high angiotensin II levels and activation of mast cells and macrophages may be critical for testicular pathogenesis. Importantly, our findings suggest that patients who become critically ill may exhibit severe alterations and harbor the active virus in the testes.