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This study investigated the effects of high compared to normal dietary salt intake on fetoplacental vascular function, activity of renin-angiotensin-aldosterone system (RAAS), placental pro- and anti-angiogenic factors and biomarkers of placental remodeling and oxidative stress during healthy uncomplicated pregnancy. Based on their 24-h sodium excretion pregnant women (37–40 weeks' gestation) were categorized into three groups: normal salt (NS, <5.75 g/day, N = 12), high salt (HS, 5.75–10.25 g/day, N = 36), and very high salt (VHS, >10.25 g/day, N = 17). Pulsatility (PI) and resistive index of middle cerebral artery (MCA) and umbilical artery, plasma renin activity (PRA), serum aldosterone, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) concentrations, as well as placental vascular endothelial growth factor C (VEGF-C), oxidative/antioxidative stress markers (TBARS/FRAP) and matrix metalloproteinase 9 (MMP-9) concentration were measured. PI MCA was significantly decreased in HS/VHS groups compared to NS group. HS/VHS intake did not suppress PRA and aldosterone concentration. Serum PlGF concentration was significantly increased while sFlt-1 concentration and sFlt-1/PlGF ratio were significantly decreased in VHS group compared to NS group. MMP-9, VEGF-C concentration, TBARS and FRAP in placental tissue were similar between study groups. HS/VHS diet does not suppress RAAS during pregnancy; however, it is associated with decreased PI MCA, a significantly decreased sFlt-1/PlGF ratio and unchanged biomarkers of placental remodeling or oxidative stress in healthy pregnant women, suggesting the presence of a possible protective or compensatory mechanism aimed at preserving placental function and pregnancy outcome itself in terms of maternal HS intake. • High-salt diet (HSD) during pregnancy affects maternal endothelial function. • However, HSD is not associated with adverse pregnancy outcome. • RAAS activity is maintained and sFlt1/PlGF reduced with HSD during pregnancy. • Biomarkers of placental remodeling and oxidative stress are not affected by maternal HSD. • Some protective or compensatory mechanisms preserve placental function during HSD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the renin-angiotensis system (RAS). Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. METHODS: Exome sequencing for a gene panel associated with renal disease was performed. The RAS was assessed by comprehensive biochemical analysis in blood. Renin expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. RESULTS: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. Angiotensin II and aldosterone in blood were not abnormally elevated. CONCLUSIONS: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension). [ABSTRACT FROM AUTHOR]

BACKGROUND: Small-interfering RNA (siRNA) targeting hepatic AGT (angiotensinogen) mRNA depletes AGT, lowering blood pressure for up to 6 months. However, certain situations may require a rapid angiotensin increase. The REVERSIR (RVR) - reverse siRNA silencing technology a potential approach to counteract siRNA effects. METHODS: Spontaneously hypertensive rats received 10 mg/kg AGT siRNA, and 3 weeks later were given AGT-RVR (1, 10, or 20 mg/kg). One week after AGT-RVR dosing, a redose of AGT siRNA assessed its post-AGT-RVR effectiveness for 2 weeks. Additionally, the impact of AGT-RVR after an equihypotensive dose of valsartan (4 mg/kg per day) was examined. RESULTS: Baseline mean arterial pressure (MAP) was 144±1 mm Hg. AGT siRNA reduced MAP by ≈16 mm Hg and AGT by >95%, while renin increased 25-fold. All AGT-RVR doses restored MAP to baseline within 4 to 7 days. Notably, 10 and 20 mg/kg restored AGT and renin to baseline, while 1 mg/kg allowed ≈50% AGT restoration, with renin remaining above baseline. A second AGT siRNA treatment, following 1 mg/kg AGT-RVR, reduced MAP to the same degree as the initial dose, while following 10 mg/kg AGT-RVR, it resulted in ≈50% of the first dose’s MAP effect at 2 weeks. The valsartan-induced MAP reduction was unaffected by AGT-RVR. CONCLUSIONS: In spontaneously hypertensive rats, angiotensinogen-RVR dose-dependently reversed AGT siRNA-induced AGT reduction, normalizing MAP. MAP normalization persisted even with 50% recovered AGT levels, likely due to upregulated renin maintaining adequate angiotensin generation. Post-AGT-RVR dosing, a second AGT siRNA dose lowered MAP again. [ABSTRACT FROM AUTHOR]

The article focuses on the SPACE trial, which examined the impact of discontinuing renin-angiotensin system inhibitors (RASI) before elective non-cardiac surgery in older patients. It aimed to assess whether stopping RASI prior to surgery would reduce postoperative myocardial injury and other adverse events. It is reported that the results showed that discontinuing RASI did not decrease the incidence of myocardial injury and may have increased the occurrence of hypertensive adverse events.

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Background: The chronic kidney disease (CKD) clinic plays a vital role in providing comprehensive ambulatory care for patients with CKD. Pharmacists contribute to ensuring proper drug use and identifying potential drug-related problems (DRPs). However, the evaluation of DRPs in the early phase of CKD clinic, particularly in resource-limited countries, remains limited. Objective: This study aimed to assess the prevalence of DRPs in CKD patients attending a CKD clinic, investigate the associated drug categories, and identify factors contributing to DRPs in CKD patients. Methods: A cross-sectional study was conducted from January 2020 to June 2021 among CKD patients attending a CKD clinic. Patient information records were used to collect demographic and relevant CKD data. A checklist for DRPs related to CKD progression and complications was utilized. Eight categories of unmet DRPs were examined. Multiple linear regression was used to investigate the relationship between pre-defined factors and the number of DRPs per patients. Results: The study included 80 patients with a total of 1,073 prescribed medications. The mean age was 73.1 ± 10.0 years, and the mean estimated glomerular filtration rate (eGFR) was 43.4± 12.9 mL/min/1.73 m². A total of 269 DRPs (25.1% of prescriptions) were identified, primarily involving the need for additional drug therapy (14.9%), dosage too high (6.3%), and inappropriate drug therapy (1.5%). Notably, renin-angiotensin-aldosterone system (RAAS) blockers were frequently omitted when indicated. NSAID use, non-compliance, and drug interactions were notable issues. The significant predictor of DRPs was the number of medications more than 7 items (ß = 0.258, P = 0.02). Conclusions: Implementing medication optimization in CKD care involving multidisciplinary teams and pharmacists is essential. Our study highlights the importance of ACEIs/ARBs, dosage adjustments, avoiding nephrotoxic agents, addressing non-compliance, and managing drug interactions for improved CKD care. The study identifies polypharmacy as a significant predictor of DRPs among CKD patients, facilitating targeted interventions for at-risk patients. [ABSTRACT FROM AUTHOR]

Many patients presenting for surgery are established on anti-hypertensive medication or may require additional manipulation of blood pressure perioperatively. This article aims to explore the pharmacology of antihypertensives in relation to cardiovascular physiology, focusing on the effects on the renin–angiotensin system and the autonomic nervous system. The most recent guidance for the stepwise treatment for hypertension is reviewed, aiming to provide anaesthetists with the relevant knowledge to manage hypertensive patients perioperatively. [ABSTRACT FROM AUTHOR]

BACKGROUND: High circulating DPP3 (dipeptidyl peptidase 3) has been associated with poor prognosis in critically ill patients with circulatory failure. In such situation, DPP3 could play a pathological role, putatively via an excessive angiotensin peptides cleavage. Our objective was to investigate the hemodynamics changes induced by DPP3 in mice and the relation between the observed effects and renin–angiotensin system modulation. METHODS: Ten-week-old male C57Bl/6J mice were subjected to intravenous injection of purified human DPP3 or an anti-DPP3 antibody (procizumab). Invasive blood pressure and renal blood flow were monitored throughout the experiments. Circulating angiotensin peptides and catecholamines were measured and receptor blocking experiment performed to investigate the underlying mechanisms. RESULTS: DPP3 administration significantly increased renal blood flow, while blood pressure was minimally affected. Conversely, procizumab led to significantly decreased renal blood flow. Angiotensin peptides measurement and an AT1R (angiotensin II receptor type 1) blockade experiment using valsartan demonstrated that the renovascular effect induced by DPP3 is due to reduced AT1R activation via decreased concentrations of circulating angiotensin II, III, and IV. Measurements of circulating catecholamines and an adrenergic receptor blockade by labetalol demonstrated a concomitant catecholamines release that explains blood pressure maintenance upon DPP3 administration. CONCLUSIONS: High circulating DPP3 increases renal blood flow due to reduced AT1R activation via decreased concentrations of circulating angiotensin peptides while blood pressure is maintained by concomitant endogenous catecholamines release. [ABSTRACT FROM AUTHOR]

Renin was discovered more than a century ago. Since then, the functions of the renin–angiotensin system in the kidney have been the focus of intensive research revealing its importance in regulation of renal physiology and in the pathogenesis of heart, vascular, and kidney diseases. Inhibitors of renin–angiotensin system components are now foundational therapies for a range of kidney and cardiovascular diseases from hypertension to heart failure to diabetic nephropathy. Despite years of voluminous research, emerging studies continue to reveal new complexities of the regulation of the renin–angiotensin system within the kidney and identification of nonclassical components of the system like the prorenin receptor (PRR) and ACE2 (angiotensin-converting enzyme 2), with powerful renal effects that ultimately impact the broader cardiovascular system. With the emergence of a range of novel therapies for cardiovascular and kidney diseases, the importance of a detailed understanding of the renin–angiotensin system in the kidney will allow for the development of informed complementary approaches for combinations of treatments that will optimally promote health and longevity over the century ahead. [ABSTRACT FROM AUTHOR]

Sodium is the main osmotically active ion in the extracellular fluid and its concentration goes hand in hand with fluid volume. Under physiological conditions, homeostasis of sodium and thus amount of fluid is regulated by neural and humoral interconnection of body tissues and organs. Both heart and kidneys are crucial in maintaining volume status. Proper kidney function is necessary to excrete regulated amount of water and solutes and adequate heart function is inevitable to sustain renal perfusion pressure, oxygen supply etc. As these organs are bidirectionally interconnected, injury of one leads to dysfunction of another. This condition is known as cardiorenal syndrome. It is divided into five subtypes regarding timeframe and pathophysiology of the onset. Hemodynamic effects include congestion, decreased cardiac output, but also production of natriuretic peptides. Renal congestion and hypoperfusion leads to kidney injury and maladaptive activation of renin-angiotensin-aldosterone system and sympathetic nervous system. In cardiorenal syndromes sodium and water excretion is impaired leading to volume overload and far-reaching negative consequences, including higher morbidity and mortality of these patients. [ABSTRACT FROM AUTHOR]

Obesity is the most common health issue in women of reproductive age, which profoundly affects maternal-fetal health. Despite progress in understanding key inflammatory and metabolic changes, the pathogenesis of the cardiovascular phenotype of obese pregnant women remains to be fully understood. This study aimed at: (i) evaluating the changes of the renin-angiotensin system (RAS) throughout pregnancy in obese vs normal weight (control) women, and (ii) evaluating the presence of any associations between maternal hemodynamic status and RAS changes. Thirty-eight normal weight and nineteen obese pregnant women were included. Clinical assessment, blood samples and maternal hemodynamic evaluation were performed at 12, 20, 30, and 36 weeks, while ultrasound assessment was scheduled at 20, 30, and 36 weeks of gestation. Measurements of sFlt-1, PlGF, Angiotensinogen, Renin, AngII, Ang1-7, ACE and ACE2 were performed by ELISA. Our data show that normotensive obese women had lower placental blood supply, as assessed by UV-Q and UV-Q/EFW, as compared to controls, and significantly higher levels of AngII and AngII/Ang1-7 ratio, which were inversely related to placental blood supply. Our study shows for the first time that normotensive obese women exhibited a significant progressive increase of AngII and AngII/Ang1-7 throughout pregnancy, which were inversely related to placental blood supply as assessed by UV-Q and UV-Q/EFW. Our data shed light on the early changes in pregnant obese women and suggest that RAS dysregulation is a prerequisite rather than a consequence of hypertensive disorders of pregnancy and other maternal neonatal complications. • Angiotensin II significantly increased in normotensive obese pregnant women and this was related to placental blood supply. • Placental blood supply was reduced in normotensive obese pregnant women at 30 weeks of gestation. • Our data suggest that RAS dysregulation may be a prerequisite of hypertensive disorders of pregnancy in obesity. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme 2 (ACE2), one of the key enzymes of the renin-angiotensin system (RAS), plays an important role in SARS-CoV-2 infection by functioning as a virus receptor. Angiotensin peptides Ang I and Ang II, the substrates of ACE2, can modulate the binding of SARS-CoV-2 Spike protein to the ACE2 receptor. In the present work, we found that co-incubation of HEK-ACE2 and Vero E6 cells with the SARS-CoV-2 Spike pseudovirus (PVP) resulted in stimulation of the virus entry at low and high micromolar concentrations of Ang I and Ang II, respectively. The potency of Ang I and Ang II stimulation of virus entry corresponds to their binding affinity to ACE2 catalytic pocket with 10 times higher efficiency of Ang II. The Ang II induced mild increase of PVP infectivity at 20 µM; while at 100 µM the increase (129.74±3.99 %) was highly significant (p<0.001). Since the angiotensin peptides act in HEK-ACE2 cells without the involvement of angiotensin type I receptors, we hypothesize that there is a steric interaction between the catalytic pocket of the ACE2 enzyme and the SARSCoV-2 S1 binding domain. Oversaturation of the ACE2 with their angiotensin substrate might result in increased binding and entry of the SARS-CoV-2. In addition, the analysis of angiotensin peptides metabolism showed decreased ACE2 and increased ACE activity upon SARS-CoV-2 action. These effects should be taken into consideration in COVID-19 patients suffering from comorbidities such as the over-activated renin-angiotensin system as a mechanism potentially influencing the SARS-CoV-2 invasion into recipient cells. [ABSTRACT FROM AUTHOR]

β-arrestins are a family of intracellular signaling proteins that play a key role in regulating the activity of G proteincoupled receptors. The angiotensin-II type 1 receptor is an important G protein-coupled receptor involved in the regulation of cardiovascular function and has been implicated in the progression of cardiovascular diseases. In addition to canonical G protein signaling, G protein-coupled receptors including the angiotensin-II type 1 receptor can signal via β-arrestin. Dysregulation of β-arrestin signaling has been linked to several cardiovascular diseases including hypertension, atherosclerosis, and heart failure. Understanding the role of β-arrestins in these conditions is critical to provide new therapeutic targets for the treatment of cardiovascular disease. In this review, we will discuss the beneficial and maladaptive physiological outcomes of angiotensin-II type 1 receptor-dependent β-arrestin activation in different cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene is a key component of the Renin-Angiotensin-Aldosterone System (RAAS). It has been proposed as an independent factor for hypertension and other cardiovascular diseases. Consequently, it has been extensively studied in various populations. The aim of this study is to investigate I/D polymorphism of ACE gene and its connection to hypertension in population of Tuzla Canton (Bosnia & Herzegovina). The study included 60 hypertensive subjects and 60 healthy control subjects with no risk factors for hypertension. I/D polymorphism was genotyped by polymerase chain reaction followed by gel electrophoresis and data obtained were statistically analysed using Chi square test. Odd's ratios were calculated with a 95% confidence interval. P-value <0.05 was considered significant. Odd's ratios were calculated with a 95% confidence interval. P-value <0.05 was considered significant. Higher frequency of genotype D/D and allele D was determined in subjects with hypertension compared to control subjects but there is no statistical significance (p>0.05). However, statistically significant association was found in compared groups of subjects with genotypes DD + ID, in regards to genotype I/I (p<0.05). The results indicate the conclusion that ACE I/D polymorphism cannot be considered the main risk factor for development of hypertension, but its influence should be investigated together with other genetic and acquired risk factors that are associated with hypertension. This research contributes to the ongoing exploration of molecular-genetic associations with hypertension. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer is a huge therapeutic and financial problem for which approved treatments have already achieved their limit of efficiency. A cost-effective strategy to extend therapeutic options in this malignancy is drug repurposing aimed at overcoming chemoresistance. Here, angiotensin-converting enzyme inhibitors (ACE-I) are worth considering. Materials and methods: We searched literature for publications supporting the idea of adjuvant application of ACE-Is in ovarian malignancy. Then, we searched The Cancer Genome Atlas databases for relevant alternations of gene expression patterns. We also performed in silico structure-activity relationship evaluation for predicting ACE-Is’ cytotoxicity against ovarian cancer cell lines. Finally, we reviewed the potential obstacles in ACE-Is repurposing process. Results: The alternation of angiotensin receptor expression in ovarian cancer translates into poorer patient survival. This confirms the participation of the renin-angiotensin system in ovarian carcinogenesis. In observational studies, ACE-Is were shown synergize with both, platinum-based chemotherapy as well as with antiangiogenic therapy. Consistently, our in silico simulation showed that ACE-Is are probably cytotoxic against ovarian cancer cells. However, the publications on their chemopreventive properties were inconclusive. In addition, some reports correlated ACE-Is use with increased general cancer incidence. We hypothesized that this effect could be associated with mutagenic nitrosamine formation in ACE-Is’ pharmaceutical formulations, as was the case with angiotensin receptor blockers (ARBs) and other well-established pharmaceuticals. Conclusions: Available data warrant further research into repositioning ACE-Is to ovarian cancer as chemosensitizers. Prior to this, however, a special research program is needed to detect possible genotoxic contaminants of ACE-Is. [ABSTRACT FROM AUTHOR]

Nearly 500 000 individuals are treated with maintenance hemodialysis for kidney failure in the United States, and roughly half will die of cardiovascular causes. Hypertension, an important and modifiable risk factor for cardiovascular disease, is observed in >80% of patients treated with maintenance hemodialysis. The pathophysiology of hypertension in patients treated with maintenance hemodialysis is multifactorial and differs from that seen in other patient populations. Factors that contribute to hypertension in patients treated with hemodialysis include volume overload, arterial stiffness, enhanced activity of the sympathetic nervous and renin-angiotensin-aldosterone systems, endothelial dysfunction, and use of erythropoietin-stimulating agents. This scientific statement reviews the current evidence on defining, diagnosing, and treating hypertension in patients treated with maintenance hemodialysis and highlights opportunities for future investigation, including studies on blood pressure targets and treatment strategies. [ABSTRACT FROM AUTHOR]

There is increasing interest in the long-term cardiovascular health of women with complicated pregnancies and their affected offspring. Emerging antenatal risk factors such as preeclampsia appear to increase the risk of hypertension and cardiovascular disease across the life course in both the offspring and women after pregnancy. However, the antenatal programming mechanisms responsible are complex and incompletely understood, with roots in alterations in the development, structure, and function of the kidney, heart, vasculature, and brain. The renin-angiotensin-aldosterone system is a major regulator of maternal-fetal health through the placental interface, as well as kidney and cardiovascular tissue development and function. Renin-angiotensin-aldosterone system dysregulation plays a critical role in the development of pregnancy complications such as preeclampsia and programming of long-term adverse cardiovascular health in both the mother and the offspring. An improved understanding of antenatal renin-angiotensin-aldosterone system programming is crucial to identify at-risk individuals and to facilitate development of novel therapies to prevent and treat disease across the life course. Given the inherent complexities of the renin-angiotensin-aldosterone system, it is imperative that preclinical and translational research studies adhere to best practices to accurately and rigorously measure components of the renin-angiotensin-aldosterone system. This comprehensive synthesis of preclinical and translational scientific evidence of the mechanistic role of the renin-angiotensin-aldosterone system in antenatal programming of hypertension and cardiovascular disease will help (1) to ensure that future research uses best research practices, (2) to identify pressing needs, and (3) to guide future investigations to maximize potential outcomes. This will facilitate more rapid and efficient translation to clinical care and improve health outcomes. [ABSTRACT FROM AUTHOR]

• sFlt-1/PlGF ratio could be a useful tool for differential diagnosis and/or adequate counseling among cases of COVID-19 and PE, especially if severe disease. • sFlt-1/PlGF ratio was significantly higher in the COVID-19-positive cases with diagnosis of PE compared to COVID-19-positive cases without PE. • COVID-19 early in pregnancy could potentially be a risk factor for preeclampsia later during gestation. To analyze soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factors (PlGF) concentrations and their ratio in pregnant and postpartum women with suspected COVID-19, and further investigate conditions associated with an increased ratio (sFlt-1/PlGF > 38), including preeclampsia (PE) and severe acute respiratory syndrome (SARS). The present study is a secondary analysis of a prospective cohort. Blood samples were collected at time of COVID-19 investigation and the serum measurements of sFlt-1 and PlGF were performed. Clinical background, SARS-CoV-2 infection characteristics, maternal and perinatal outcomes were further analyzed. Serum measurements of sFlt-1 and PlGF; obstetrics and clinical outcomes. A total of 97 SARS-CoV-2 unvaccinated women with suspected infection were considered, 76 were COVID-19 positive cases and 21 COVID-19 negative. Among COVID-19 positive cases, 09 presented with SARS and 11 were diagnosed with PE, of which 6 had SARS-CoV-2 infection in first and second trimester (04 with sFlt-1/PlGF ≥ 38) and 05 with PE and COVID-19 diagnosed at the same time, during third trimester (03 with sFlt-1/PlGF ≥ 38). Five presented with PE with severe features. sFlt-1/PlGF ratio was significantly higher in the COVID-19 positive/PE positive group compared to COVID-19 positive/PE negative group (p-value = 0.005), with no increase in cases complicated by SARS. sFlt-1/PlGF ratio could be a useful tool for differential diagnosis and adequate counseling among cases of COVID-19 and PE, especially if severe disease. COVID-19 early in pregnancy could potentially be a risk factor for PE later during gestation. [ABSTRACT FROM AUTHOR]

Background: Describing the antihypertensive medication regimens used in the SPRINT (Systolic Blood Pressure Intervention Trial) would contextualize the standard and intensive systolic blood pressure (SBP) interventions and may inform future implementation efforts to achieve population-wide intensive SBP goals. Methods: We included SPRINT participants with complete medication data at the prerandomization and 12-month visits. Regimens were categorized by antihypertensive medication class. Analyses were stratified by treatment group (standard goal SBP <140 mm Hg versus intensive goal SBP <120 mm Hg). Results: Among 7860 participants (83.7% of 9361 randomized), the median number of classes used at the prerandomization visit was 2.0 and 2.0 in the standard and intensive groups (P =0.559). At 12-months, the median number of classes used was 3.0 and 2.0 in the intensive and standard groups (P <0.001). Prerandomization, angiotensin-converting enzyme inhibitor (ACE), or angiotensin-II receptor blocker (ARB) monotherapy was the most common regimen in the intensive and standard groups (12.6% versus 12.2%). At 12-months, ACE/ARB monotherapy was still the most common regimen among standard group participants (14.7%) and was used by 5.3% of intensive group participants. Multidrug regimens used by the intensive and standard participants at 12 months were as follows: an ACE/ARB with thiazide (12.2% and 7.9%); an ACE/ARB with calcium channel blocker (6.2% and 6.8%); an ACE/ARB, thiazide, and calcium channel blocker (11.4% and 4.3%); and an ACE/ARB, thiazide, calcium channel blocker, and beta-blocker (6.5% and 1.2%). Conclusions: SPRINT investigators favored combining ACEs or ARBs, thiazide diuretics, and calcium channel blockers to target SBP <120 mm Hg, compared to ACE/ARB monotherapy to target SBP <140 mm Hg. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01206062. [ABSTRACT FROM AUTHOR]

Inducible NO synthase (NOS II) was proposed to play an important role in salt resistance of Dahl salt-resistant (SR/Jr) rats. Its chronic inhibition by specific inhibitors was accompanied by blood pressure (BP) elevation in animals subjected to high salt intake. The aim of our study was to evaluate 1) whether such inhibitors affect BP and/or its particular components (sympathetic tone and NO-dependent vasodilation) only under the conditions of high salt intake, and 2) whether similar BP effects are elicited after systemic or intracerebroventricular (icv) application of these inhibitors. Wistar rats fed Altromin diet (0.45 % NaCl) and SR/Jr rats fed either a low-salt (LS, 0.3 % NaCl) or a high-salt (HS, 4 % NaCl) diet were studied. Aminoguanidine (AMG) and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT) were used as NOS II inhibitors. BP and its responses to acute blockade of renin-angiotensin system (captopril), sympathetic nervous system (pentolinium) and NO synthase (L-NAME) were measured in conscious cannulated rats. There were no significant changes of BP or its components in either Wistar rats or SR/Jr rats subjected to chronic inhibition of NOS II by peroral aminoguanidine administration (50 mg/kg/day for 4 weeks). This was true for SR/Jr rats fed either LS or HS diets. Furthermore, we have studied BP effects of chronic icv administration of both NOS II inhibitors in SR/Jr rats fed HS diet, but we failed to find any BP changes elicited by such treatment. In conclusion, inducible NO synthase does not participate in the resistance of SR/Jr rats to hypertensive effects of excess salt intake. [ABSTRACT FROM AUTHOR]

The renin angiotensin system (RAS) has been studied for its effects on various neurological disorders. The identification of functional receptors for Ang-(1–7) and Ang II peptides in astrocytes highlights the physiological modulation and the important role of these cells in the central nervous system. The present study aims to understand the role of RAS peptides, particularly Ang-(1–7) and Ang II, in the secretion of trophic factors by astrocytes and their effects on hippocampal neurons. We used primary cultures of astrocytes and neurons from the hippocampus of either sex neonate of Wistar strain rats. In the present study, we demonstrated that the treatment of astrocytes with Ang-(1–7) acts on the modulation of these cells, inducing reactive astrogliosis, identified through the increase in the expression of GFAP. Furthermore, we obtained a conditioned medium from astrocytes treated with Ang-(1–7), which in addition to promoting the secretion of neurotrophic factors essential for neuronal-glial interactions that are fundamental for neuritogenesis and neuronal survival, showed a neuroprotective effect against glutamatergic excitotoxicity. In turn, Ang II does not exhibit the same effects on astrocyte modulation, exacerbating deleterious effects on brain RAS. Neuron-astrocyte interactions have been shown to be an integral part of the central effects mediated by RAS, and this study has significantly contributed to the understanding of the biochemical mechanisms involved in the functioning of this system. [ABSTRACT FROM AUTHOR]

• SARS-CoV2 entry in the cells reduces ACE2 levels; • Reduced ACE2 levels leads to increase BK and DABK contributing to the BK and cytokine storm; • Inflammation leads to increase in sPLA2 and AA resulting in TXA2 secretion. • TXA2 leads to platelet aggreagation and more TXA2 secretion in a positive loop. • Mastocyte activation releases heparin, contributing to the thrombotic state. In this article we present a hypothesis based on the relationship between four physiological systems: the renin-angiotensin system (RAS), the kallikrein-kinin system (KKS), the arachidonic acid (AA) cascade, and platelet aggregation/coagulation − in the context of COVID-19. The central point of our proposition relies on ACE 2 levels, which reduce following SARS-CoV-2 entry in the cell. The following cascade of events. Triggered by this reduction, involves the increase in Ang II levels and its consequent binding to AT1-R, initiating the release of pro-inflammatory cytokines such as TNF-α, IL-1, IL-10, and IL-12. These pro-inflammatory cytokines activate immune cells, including mast cells, which release heparin, thus activating Coagulation factor XII and increasing pre-kallikrein (PK) production. Consequently, there is an increase in bradykinin (BK) levels. BK, via its receptor BKB2-R, induces Ca2 + release increasing secreted phospholipase A 2 (sPLA 2) levels. Concomitantly, both the imbalance in Ang II/AT1-R and BK/BKB2-R signaling contribute to sPLA 2 activation, inducing the release of arachidonic acid (AA) from cell membrane phospholipids, by cyclooxygenase-2 (COX-2) cleavage to produce prostaglandin G 2 (PGG 2), and later prostaglandin H 2 (PGH 2). At least, PGH 2 is converted to thromboxane A 2 (TXA 2), which is involved in the platelet aggregation process. Platelet aggregation further increases TXA 2 levels, initiating a positive feedback loop leading to further platelet activation and clot formation. Ultimately, this cascade of events may contribute to the development of a pre-thrombotic state and increase the risk of mortality, in COVID-19. We believe that this integrated approach could provide a deeper understanding of the underlying mechanisms of COVID-19 and guide future therapeutic strategies. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel peptide SSA was isolated using α-chymotrypsin from Sebastes schlegelii. • SSA binds to angiotensin converting enzyme and converting enzyme to inhibit angiotensin 2 synthesis. • SSA reduces the concentration of angiotensin 2 in the body and prevents damage to the heart and blood vessels caused by high blood pressure. • Peptides isolated from SSA bind to the active site of angiotensin converting enzyme and inhibit synthesis with angiotensin. 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. [ABSTRACT FROM AUTHOR]

Objectives: Preeclampsia is a life-threatening disorder of pregnancy unique to humans. Poor placentation in the first trimester of pregnancy is widely accepted to be an underlying cause of preeclampsia. Galectin-7 is abnormally elevated in chorionic villous samples and serum from women that subsequently develop pre-term preeclampsia. Administration of exogenous galectin-7 to pregnant mice causes preeclampsia-like features (hypertension, proteinuria), associated with dysregulation of the renin-angiotensin system (RAS). In this study investigated the mechanism by which galectin-7 induces alterations to tissue RAS homeostasis and ROS production. We hypothesized that galectin-7 induces alterations in the production of either placental RAS or NADPH oxidases (or both) to drive the dysregulated RAS and ROS production seen in preeclampsia.Study Design: Mated female mice (n = 5-6/group) received single (embryonic day [E]12/13) or multiple (E8-12) subcutaneous injections of 400 μg/kg/day galectin-7 or vehicle control and killed on E13 or E18. Human first trimester placental villous and decidual tissue (n = 11) was cultured under 8 % oxygen with 1 µg/mL galectin-7 or vehicle control for 16 h.Results: Galectin-7 administration to pregnant mice impaired placental labyrinth formation, suppressed circulating aldosterone and altered placental RAS (Agt, Renin) and NADPH oxidase (Cyba, Cybb and Icam1) mRNA expression. In vitro, galectin-7 regulated human placental villous RAS (AGT) and NADPH oxidase (CYBA, ICAM1 and VCAM1) mRNA expression.Conclusions: Overall, galectin-7 likely drives hypertension in preeclampsia via its direct regulation of multiple pathways associated with preeclampsia in the placenta. Galectin-7 may therefore be a therapeutic target to improve placental function and prevent preeclampsia. [ABSTRACT FROM AUTHOR]

The agonists of a2-adrenergic receptors such as clonidine, rilmenidine or monoxidine are known to lower blood pressure (BP) through a reduction of brain sympathetic outflow but their chronic antihypertensive effects in rats with low-renin or highrenin forms of experimental hypertension were not studied yet. Moreover, there is no comparison of mechanisms underlying BP reduction elicited by chronic peroral (po) or intracerebroventricular (icv) clonidine treatment. Male salt-sensitive Dahl rats fed a high-salt (4% NaCl) diet and Ren-2 transgenic rats were treated with clonidine administered either in the drinking fluid (0.5 mg/kg/day po) or as the infusion into lateral brain ventricle (0.1 mg/kg/day icv) for 4 weeks. Basal BP and the contributions of renin-angiotensin system (captopril 10 mg/kg iv) or sympathetic nervous system (pentolinium 5 mg/kg iv) to BP maintenance were determined in conscious cannulated rats at the end of the study. Both peroral and intracerebroventricular clonidine treatment lowered BP to the same extent in either rat model. However, in both models chronic clonidine treatment reduced sympathetic BP component only in rats treated intracerebroventricularly but not in perorally treated animals. In contrast, peroral clonidine treatment reduced angiotensin IIdependent vasoconstriction in Ren-2 transgenic rats, whereas it lowered residual blood pressure in Dahl rats. In conclusions, our results indicate different mechanisms of antihypertensive action of clonidine when administered centrally or systemically. [ABSTRACT FROM AUTHOR]

Background: Ion channel mutations in calcium regulating genes strongly associate with AngII (angiotensin II)-independent aldosterone production. Here, we used an established mouse model of in vivo aldosterone autonomy, Cyp11b2-driven deletion of TWIK-related acid-sensitive potassium channels (TASK-1 and TASK-3, termed zona glomerulosa [zG]-TASK-loss-of-function), and selective pharmacological TASK channel inhibition to determine whether channel dysfunction in native, electrically excitable zG cell rosette-assemblies: (1) produces spontaneous calcium oscillatory activity and (2) is sufficient to drive substantial aldosterone autonomy.Methods: We imaged calcium activity in adrenal slices expressing a zG-specific calcium reporter (GCaMP3), an in vitro experimental approach that preserves the native rosette assembly and removes potentially confounding extra-adrenal contributions. In parallel experiments, we measured acute aldosterone production from adrenal slice cultures.Results: Absent from untreated WT slices, we find that either adrenal-specific genetic deletion or acute pharmacological TASK channel inhibition produces spontaneous oscillatory bursting behavior and steroidogenic activity (2.4-fold) that are robust, sustained, and equivalent to activities evoked by 3 nM AngII in WT slices. Moreover, spontaneous activity in zG-TASK-loss-of-function slices and inhibitor-evoked activity in WT slices are unresponsive to AngII regulation over a wide range of concentrations (50 pM to 3 µM).Conclusions: We provide proof of principle that spontaneous activity of zG cells within classic rosette assemblies evoked solely by a change in an intrinsic, dominant resting-state conductance can be a significant source of AngII-independent aldosterone production from native tissue. [ABSTRACT FROM AUTHOR]

Background: Increased arterial stiffness is associated with adverse cardiovascular outcomes. We studied the sex-specific impact of angiotensin antagonists on vascular function in hypertension with the hypothesis that their effects on arterial stiffness may be variable in men and women.Methods: In 141 hypertensive participants with mild cognitive impairment (age 65.9±7.7, 57% female), candesartan (up to 32 mg, n=77) or lisinopril (up to 40 mg, n=64) were administered to achieve blood pressure <140/90 mm Hg. Pulse wave velocity, central pulse pressure, and central augmentation index were measured using applanation tonometry (SphygmoCor, Australia). Multivariate linear regression and mixed model analyses were performed using intention-to-treat and per protocol analyses for those completing the study.Results: Blood pressure reduction was similar among candesartan and lisinopril groups. Compared with candesartan, lisinopril therapy resulted in lower pulse wave velocity (0.5±0.8 versus -0.7±0.4 m/s, respectively; P=0.003) and central pulse pressure (-1±3 versus -7±4 mm Hg; P=0.03) after 1 year. There was a significant interaction by sex whereby the improvements in pulse wave velocity and central pulse pressure with lisinopril compared with candesartan were only observed in women. In contrast, there was greater improvement in augmentation index with candesartan compared with lisinopril (-4±7% versus -1.5±8%; P=0.05), with no sex differences.Conclusions: Despite equipotent antihypertensive effects, lisinopril was more effective than candesartan at lowering arterial stiffness in women. In contrast, candesartan was more effective than lisinopril in improving pulse wave reflections in both sexes. These findings demonstrate differential sex-specific effects of renin-angiotensin system antagonists on arterial function in hypertension that may contribute to long-term cardiovascular and neurocognitive outcomes in this population. [ABSTRACT FROM AUTHOR]

Background: Approximately 10% of infants are born preterm. Preterm birth leads to short and long-term changes in cardiac shape and function. By using a rat model of neonatal high-oxygen (80%O2) exposure, mimicking the premature hyperoxic transition to the extrauterine environment, we revealed a major role of the renin-angiotensin system peptide Angio II (angiotensin II) and its receptor AT1 (angiotensin receptor type 1) on neonatal O2-induced cardiomyopathy. Here, we tested whether treatment with either orally active compounds of the peptides Angio-(1-7) or alamandine included in cyclodextrin could prevent postnatal cardiac remodeling and the programming of cardiomyopathy induced by neonatal high-O2 exposure.Methods: Sprague-Dawley pups were exposed to room air or 80% O2 from postnatal day 3 (P3) to P10. Neonatal rats were treated orally from P3 to P10 and assessed at P10 and P28. Left ventricular (LV) shapes were characterized by tridimensional computational atlases of ultrasound images in addition to histomorphometry.Results: At P10, high O2-exposed rats presented a smaller, globular and hypertrophied LV shape versus controls. Treatment with cyclodextrin-Angio-(1-7) significantly improved LV function in the O2-exposed neonatal rats and slightly changed LV shape. Cyclodextrin-alamandine and cyclodextrin-Angio-(1-7) treatments similarly reduced hypertrophy at P10 as well as LV remodeling and dysfunction at P28. Both treatments upregulated cardiac angiotensin-converting enzyme 2 in O2-exposed rats at P10 and P28.Conclusions: Our findings demonstrate LV remodeling changes induced by O2-stress and the potential benefits of treatments targeting the cardioprotective renin-angiotensin system axis, supporting the neonatal period as an important window for interventions aiming at preventing cardiomyopathy in people born preterm. [ABSTRACT FROM AUTHOR]

Background: Diabetes, hypertension, and hyperlipidemia have been identified as common modifiable risk factors of cardiovascular disease, frequently occurring together, especially among older people. Medication adherence to concomitant triple therapy is of vital importance among this population.Objectives: The objective of the current study was to examine adherence to concurrent oral antidiabetics, renin-angiotensin system antagonists, and statins (triple therapy) among older patients and further evaluate the predictors associated with adherence to concurrent triple therapy among older patients.Methods: Patients on concurrent triple therapy were identified using a Texas Medicare Advantage dataset. Patients had to have an overlap of 30 days of triple therapy and a second prescription of each component of triple therapy within the identification period. Medication adherence was measured using Proportion of Days Covered during the 1-year follow-up period to determine different adherence groups. A multinomial logistic regression was further conducted to determine various demographic and clinical factors associated with each adherence group.Results: The final patient cohort comprised 7847 patients. Of these, 68.05% were adherent to triple therapy, 21.43% were adherent to double therapy, and 10.51% were adherent to monotherapy or none. Compared with the triple therapy adherent group, females had a higher likelihood of being in the triple therapy nonadherent groups, while a refill of 90 days or more and prevalent use of triple therapy was associated with a lower likelihood of being in the triple therapy nonadherent groups. Finally, predictors associated with the adherent to monotherapy or none group included older age and a higher number of total other medications.Conclusion: Adherence to triple therapy among older patients was 68.05%, and several demographic and clinical factors were associated with the different adherence groups. [ABSTRACT FROM AUTHOR]

One of the most frequent in-hospital electrolyte disturbances is hyponatremia. Hyponatremia in heart failure (HF) is mainly associated with hypervolemia resulting from activation of baroreceptor-mediated hormones, such as arginine vasopressin (AVP), renin–angiotensin–aldosterone system, and catecholamines. Various electrolyte imbalance can occur as heart failure progress. The goal of this review was to outline the current literature on hyponatremia in HF patients. [ABSTRACT FROM AUTHOR]

[Display omitted] • DOCA-salt hypertension promotes loss of the anticontractile effect of m PVAT in resistance arteries. • EWH prevents the m PVAT damage caused by DOCA-salt hypertension. • EWH modulates RAS axis and reduces redox balance and inflammatory state in DOCA-salt hypertensive rats. 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 (m PVAT) were used for functional, molecular, and biochemical analysis. The anticontractile effect of m PVAT 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 m PVAT 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 m PVAT of DOCA-salt rats; while did not change AT1R expression, but increased AT2R expression. In m PVAT, 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. [ABSTRACT FROM AUTHOR]

The activation of the Renin Angiotensin System (RAS) is required during pregnancy and it seems that RAS dysfunction has some important effects on pathological pregnancy conditions, including preeclampsia (PE). The objective of this review is to summarize and to discuss the role of the RAS in normal pregnancy and in PE. We found evidence that the RAS is important for the evolution of pregnancy under physiological conditions and plays an important role in the pathogenesis of PE. In normal gestation, almost all circulating components of RAS are increased and there is a general state of non-reactivity to the vasoconstrictor actions of Angiotensin (Ang) II. In PE, changes in the circulating levels of RAS components occur, especially with an intense decrease in the levels of Ang I, Ang II and Ang-(1-7). Our findings endorse the idea that PE is a disease whose cornerstone relies on altered placental physiology. There are high tissue levels of Ang II type 1 receptor (AT1R) in the musculature of the blood vessels and in the placenta, generating a state of increased sensitivity to the vasoconstrictor action of Ang II. AT1R autoantibodies (AT1R-AA) might be one of the key points for the vicious cycle of PE, as these molecules are synthesized in situations of hypoxia and enhance placental vasoconstriction, causing even more hypoxia. Further studies are needed to investigate the role of circulating RAS, uteroplacental RAS and local RAS molecules from other tissues related to the pathogenesis of PE. [ABSTRACT FROM AUTHOR]

Background: The collecting duct (CD) is a major site of both biosynthesis and action of prostaglandin E2 as highlighted by the predominant expression of COX-2 (cyclooxygenase-2) and some E-prostanoid (EP) subtypes at this nephron site. The purpose of this study was to determine the relevance and mechanism of CD COX-2/prostaglandin E2/EP1 signaling for the regulation of Na+ hemostasis during Na+ depletion.Methods: Mice with Aqp2Cre-driven deletion of COX-2 (COX-2fl/flAqp2Cre+) or the EP1 subtype (EP1fl/flAqp2Cre+) were generated and the Na+-wasting phenotype of these mice during low-salt (LS) intake was examined. EP subtypes responsible for prostaglandin E2-induced local renin response were analyzed in primary cultured mouse inner medullary CD cells.Results: Following 28-day LS intake, COX-2fl/flAqp2Cre+ mice exhibited a higher urinary Na+ excretion and lower cumulative Na+ balance, accompanied with suppressed intrarenal renin, AngII (angiotensin II), and aldosterone, expression of CYP11B2 (cytochrome P450 family 11 subfamily B member 2), and blunted expression of epithelial sodium channel subunits compared to floxed controls (COX-2fl/flAqp2Cre-), whereas no differences were observed for indices of systemic renin-angiotensin-aldosterone system. In cultured CD cells, exposure to prostaglandin E2 stimulated release of soluble (pro)renin receptor, prorenin/renin and aldosterone and the stimulation was more sensitive to antagonism of EP1 as compared other EP subtypes. Subsequently, EP1fl/flAqp2Cre+ mice largely recapitulated Na+-wasting phenotype seen in COX-2fl/flAqp2Cre+ mice.Conclusions: The study for the first time reports that CD COX-2/EP1 pathway might play a key role in maintenance of Na+ homeostasis in the face of Na+ depletion, at least in part, through activation of intrarenal renin-angiotensin-aldosterone-system and epithelial sodium channel. [ABSTRACT FROM AUTHOR]

Background and Aims: The renin-angiotensin system (RAS), which is a key mediator of cardiovascular homeostasis, has two main axes. The classic one, including angiotensin-converting enzyme (ACE) and Angiotensin (Ang) II, promoting vasoconstriction, and the "alternative" one, including ACE2 and Ang1-7, with opposed actions to AngII. ACE2 has been identified as the main receptor of SARS-CoV2, whereby it enters the cells, leading to the downregulation of surface ACE2 and RAS tissue unbalance. Given that diabetes is associated with an increase in COVID-19 severity and death, we aimed at evaluating RAS expression in patients with type 1 diabetes (T1D).Methods and Results: This is a case-control study comparing 39 T1D patients to 33 controls, with a median age of 29 and 32 years, and no comorbidities. ACE and ACE2 gene expression was assessed in peripheral blood mononuclear cells. T1D patients had higher ACE expression and circulating AngII, which were related to glucose levels. T1D patients had lower ACE2 expression. However, ACE2 expression was also related to the sex of participants, being higher in the female group. T1D women did not show the same increase of ACE2 expression that was seen in control women.Conclusion: T1D promotes the increase of ACE, AngII, and ACE/ACE2, which might contribute to the higher cardiovascular risk, as well as to severe tissue injury induced by SARS-CoV2 in these patients. The ratio ACE/ACE2 does not differ between men and women with T1D, which might explain why CVD or COVID-19 do not show substantial gender differences in these patients. [ABSTRACT FROM AUTHOR]

Supplemental oxygen is often used to treat newborns with respiratory disorders. Exposure to high concentration of oxygen and long-term oxygen causes inflammation and acute lung injury. The acute inflammatory phase is followed by a fibroproliferative repair phase, leading to lung fibrosis. Many infants with lung fibrosis develop significant respiratory morbidities including reactive airways dysfunction and obstructive lung disease during childhood. Despite the absence of effective treatments and the incomplete understanding regarding mechanisms underlying fibrosis, extensive literature regarding lung fibrosis from in vitro and in vivo hyperoxia-exposed models is available. In this review, we discuss molecular mediators and signaling pathways responsible for increased fibroblast proliferation and collagen production, excessive extracellular matrix accumulation, and eventually, lung fibrosis. We discuss each of these mediators separately to facilitate clear understanding as well as significant interactions occurring among these molecular mediators and signaling pathways. [ABSTRACT FROM AUTHOR]

ACE (angiotensin-converting enzyme)-2 as the target for SARS-CoV-2 also negatively regulates the renin-angiotensin system. Pathological activation of ADAM17 (A disintegrin and metalloproteinase-17) may potentiate inflammation and diminish ACE2-mediated tissue protection through proteolytic shedding, contributing to SARS-CoV-2 pathogenesis. We aim to examine plasma soluble ACE2 and angiotensin profiles in relation to outcomes by enrolling consecutive patients admitted for COVID-19 with baseline blood collection at admission and repeated sampling at 7 days. The primary outcome was 90-day mortality, and secondary outcomes were the incidence of end-organ injuries. Overall, 242 patients were included, the median age was 63 (52-74) years, 155 (64.0%) were men, and 57 (23.6%) patients reached the primary end point. Baseline soluble ACE2 was elevated in COVID-19 but was not associated with disease severity or mortality. In contrast, an upward trajectory of soluble ACE2 at repeat sampling was independently associated with an elevated risk of mortality and incidence of acute myocardial injury and circulatory shock. Similarly, an increase in soluble tumor necrosis factor receptor levels was also associated with adverse outcomes. Plasma Ang I, Ang 1-7 (angiotensin 1-7) levels, and the Ang 1-7/Ang II (angiotensin II) ratio were elevated during SARS-CoV-2 infection related to downregulation of ACE activity at baseline. Moreover, patients having an upward trajectory of soluble ACE2 were characterized by an imbalance in the Ang 1-7/Ang II ratio. The observed dysregulation of ACE2 and angiotensin peptides with disease progression suggest a potential role of ADAM17 inhibition and enhancing the beneficial Ang 1-7/Mas axis to improve outcomes against SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

• Glioblastoma stem cells express renin-angiotensin system (RAS) and its bypass loops. • Patients with glioblastoma are treated with a combination of RAS modulators. • The treatment was well tolerated with low side-effects. • The treatment preserves the quality of life and performance status of the patients. • The treatment may lengthen survival time. Glioblastoma is the most common and most aggressive primary brain cancer in adults. Standard treatment of glioblastoma consisting of maximal safe resection, adjuvant radiotherapy and chemotherapy with temozolomide, results in an overall median survival of 14.6 months. The aggressive nature of glioblastoma has been attributed to the presence of glioblastoma stem cells which express components of the renin-angiotensin system (RAS). This phase I clinical trial investigated the tolerability and efficacy of a treatment targeting the RAS and its converging pathways in patients with glioblastoma. Patients who had relapsed following standard treatment of glioblastoma who met the trial criteria were commenced on dose-escalated oral RAS modulators (propranolol, aliskiren, cilazapril, celecoxib, curcumin with piperine, aspirin, and metformin). Of the 17 patients who were enrolled, ten completed full dose-escalation of the treatment. The overall median survival was 19.9 (95% CI:14.1–25.7) months. Serial FET-PET/CTs showed a reduction in both tumor volume and uptake in one patient, an increase in tumor uptake in nine patients with decreased (n = 1), unchanged (n = 1) and increased (n = 7) tumor volume, in the ten patients who had completed full dose-escalation of the treatment. Two patients experienced mild side effects and all patients had preservation of quality of life and performance status during the treatment. There is a trend towards increased survival by 5.3 months although it was not statistically significant. These encouraging results warrant further clinical trials on this potential novel, well-tolerated and cost-effective therapeutic option for patients with glioblastoma. [ABSTRACT FROM AUTHOR]

Cardiac dysfunction can be prevented by addressing risk factors including unhealthy diet with other lifestyle modifications. The present study demonstrates the effect of diet mixed with sea and table salts on cardiac remodeling with respect to CKMB, renin, angiotensin II, interleukin-6 and 10. Animals divided into six groups. Normal control, Table salt (0.3%), Natural sea salt (0.3%), Doxorubicin-induced cardiac remodeling control (2 mg/kg), + Normal table salt (0.3%) and Doxorubicin + Natural sea salt (0.3%). Serum analysis and histopathology of heart, liver and kidney was performed. Significant variation (P <.05) observed in in CKMB for Natural sea salt group compared to Normal. Significant (P <.05) variation in renin for Normal table salt group compared to Normal. Variation in interleukin-6, 10, renin and angiotensin II give new insight in these parameters with marked variation in cellular architecture of the heart, liver and kidney. Observations suggest diet with natural sea salt demonstrated significant beneficial effect on cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme 2 (ACE2) was identified as a molecule that mediates the cellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several membrane molecules of the host cell must cooperate in this process. While ACE2 serves in a membrane receptor-mediating interaction with the surface spike (S) glycoprotein of SARS-CoV-2 located on the virus envelope, enzyme A disintegrin and metalloproteinase 17 (ADAM17) regulates ACE2 availability on the membrane and transmembrane protease serine 2 (TMPRSS2) facilitates virus-cell membrane fusion. Interestingly, ACE2, ADAM17 and TMPRSS2 show a daily rhythm of expression in at least some mammalian tissue. The circadian system can also modulate COVID-19 progression via circadian control of the immune system (direct, as well as melatonin-mediated) and blood coagulation. Virus/ACE2 interaction causes ACE2 internalization into the cell, which is associated with suppressed activity of ACE2. As a major role of ACE2 is to form vasodilatory angiotensin 1-7 from angiotensin II (Ang II), suppressed ACE2 levels in the lung can contribute to secondary COVID-19 complications caused by up-regulated, pro-inflammatory vasoconstrictor Ang II. This is supported by the positive association of hypertension and negative COVID-19 prognosis although this relationship is dependent on numerous comorbidities. Hypertension treatment with inhibitors of renin-angiotensin system does not negatively influence prognosis of COVID-19 patients. It seems that tissue susceptibility to SARS-CoV-2 shows negative correlation to ACE2 expression. However, in lungs of infected patient, a high ACE2 expression is associated with better outcome, compared to low ACE2 expression. Manipulation of soluble ACE2 levels is a promising COVID-19 therapeutic strategy. [ABSTRACT FROM AUTHOR]

Aged people are the most susceptible group to COVID-19 infection. Immunosenescence characterized by impairment of immune function with inflamm-aging contributes to pathophysiological alterations, among which endocrine and metabolic diseases are not exception. Diabetes, obesity along with impairment of disorders of thyroid functions are the most frequent ones, the common feature of which is failure of immune system including autoimmune processes. In the minireview we discussed how COVID-19 and aging impact innate and adaptive immunity, diabetes and selected neuroendocrine processes. Mentioned is also beneficial effect of vitamin D for attenuation of these diseases and related epigenetic issues. Particular attention is devoted to the role of ACE2 protein in the light of its intimate link with renin-angiotensin regulating system. [ABSTRACT FROM AUTHOR]

[Display omitted] Some epidemiological studies have revealed that vitamin D (VD) deficiency is closely linked with the prevalence of obesity, however, the role of VD in energy homeostasis is yet to be investigated, especially in central nervous system. Given that VD negatively regulates renin in adipose tissue, we hypothesized that central VD might play a potential role in energy homeostasis. The present study aims to investigate the potential role of VD in energy homeostasis in the CNS and elaborate its underlying mechanisms. This study was conducted in Cyp27b1 −/− mice, VD-treated and wild-type mice. After the intraventricular injection of renin or its inhibitors, the changes of renin-angiotensin system (RAS) and its down-stream pathway as well as their effects on metabolic rate were examined. The RAS activity was enhanced in Cyp27b1 −/− mice, exhibiting a increased metabolic rate. Additionally, corticotropin-releasing hormone (CRH), a RAS-mediated protein regulating energy metabolism in the hypothalamus, increased significantly in Cyp27b1 −/− mice. While in VD-treated group, the RAS and sympathetic nerve activities were slightly inhibited, hence the reduced metabolic rate. Collectively, the present study demonstrates that the VD/vitamin D receptor (VDR) has a significant impact on energy homeostasis through the modulation of RAS activity in the hypothalamus, subsequently altering CRH expression and sympathetic nervous activity. [ABSTRACT FROM AUTHOR]

[Figure: see text]. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) has been recognized as a severe complication of diabetes mellitus and a dominant pathogeny of end-stage kidney disease, which causes serious health problems and great financial burden to human society worldwide. Conventional strategies, such as renin-angiotensin-aldosterone system blockade, blood glucose level control, and bodyweight reduction, may not achieve satisfactory outcomes in many clinical practices for DN management. Notably, due to the multi-target function, Chinese medicine possesses promising clinical benefits as primary or alternative therapies for DN treatment. Increasing studies have emphasized identifying bioactive compounds and molecular mechanisms of reno-protective effects of Chinese medicines. Signaling pathways involved in glucose/lipid metabolism regulation, antioxidation, anti-inflammation, anti-fibrosis, and podocyte protection have been identified as crucial mechanisms of action. Herein, we summarize the clinical efficacies of Chinese medicines and their bioactive components in treating and managing DN after reviewing the results demonstrated in clinical trials, systematic reviews, and meta-analyses, with a thorough discussion on the relative underlying mechanisms and molecular targets reported in animal and cellular experiments. We aim to provide comprehensive insights into the protective effects of Chinese medicines against DN. Diabetic nephropathy is one of the most severe complications of diabetes mellitus. Chinese medicines have been intensively studied in treating diabetic nephropathy. This review comprehensively summarizes and discusses the clinical efficacies and underlying mechanisms of Chinese medicines for diabetic nephropathy, providing deep insights and profound perspectives into this field. [Display omitted] [ABSTRACT FROM AUTHOR]

[Figure: see text]. [ABSTRACT FROM AUTHOR]

Background: This study investigated the expression and localization of cathepsins B, D, and G in relationship to the embryonic stem cell (ESC)-like population we have previously identified in microcystic lymphatic malformation (mLM). Methods and Results: Immunohistochemical staining demonstrated expression of cathepsins B, D, and G in cervicofacial mLM tissue samples from 11 patients. Immunofluorescence staining of two representative mLM samples showed localization of cathepsins B and D to the OCT4+ and the c-MYC+ cells on the endothelium of lesional vessels and the stroma, while cathepsin G was localized to the OCT4+/tryptase+ cells within the stroma. Transcript expression of cathepsins B, D, and G was confirmed using reverse transcription quantitative polymerase chain reaction (RT-qPCR; n = 5). Western blotting (n = 3) performed on the mLM tissue samples revealed protein expression of cathepsins B and D, which were demonstrated to be enzymatically active using enzymatic activity assays. Conclusion: This study demonstrated expression of cathepsins B and D by the ESC-like cells on the endothelium of lesional vessels and the stroma, while cathepsin G was localized to the OCT4+ phenotypic mast cells within the stroma of mLM. [ABSTRACT FROM AUTHOR]