Renin-angiotensin-aldosterone System System Research Articles

Walnut peptide relieves hypertension and associated kidney and heart injury by regulating the renin-angiotensin-aldosterone system and intestinal microbiota.

Hypertension is a chronic disease with high morbidity and mortality. Previously, we screened a walnut meal peptide FDWLR (PEP) with significant angiotensin-converting enzyme inhibitory activity. The present study further investigated the anti-hypertensive effects of PEP in vivo using spontaneously hypertensive rats. The results indicated that PEP reduced blood pressure and the indices in the renin-angiotensin-aldosterone system (RAAS) including angiotensin-converting enzyme (ACE) (decreased by 15.36%), angiotensin II (Ang II) (decreased by 31.56%), angiotensinogen (AGT) (decreased by 58.84%) and aldosterone (ALD) (decreased by 18.27%), whereas NO levels increased by 54.96%. The pathological analysis showed that PEP relieved cardiac and renal damage. PEP also alleviated oxidative stress, inflammation and fibrosis in the heart and kidney. Mechanistically, PEP mitigated cardiac and renal damage by simultaneously regulating ACE-Ang II-AT1R and the ACE2-Ang (1-7)-MAS axis. Additionally, PEP increased the levels of short chain fatty acids by 224.16% and improved gut microbiota by increasing the abundance of Prevotella, Phascolarctobacterium, Clostridium_sensu_stricto and Bifidobacterium, at the same time as decreasing Bacteroides and Alistipes abundances. This study indicated that PEP prevented hypertension and associated heart and kidney damage by modulating the RAAS system and gut microbiota, which is valuable in guiding future development and optimal utilization of walnut meal. © 2024 Society of Chemical Industry.

The mineralocorticoid system, cardiometabolic health and its interplay with adipose tissue.

The mineralocorticoid system, comprising the renin-angiotensin-aldosterone system (RAAS) and associated receptors, is traditionally viewed as a regulator of sodium and fluid balance and blood pressure (BP), with the main mineralocorticoid hormone aldosterone acting via the mineralocorticoid receptor (MR) in distal renal tubules. Over the past few decades, there has been a wider understanding of the role of the mineralocorticoid system in regulating both classical BP-dependent and non-BP-dependent systemic effects. Mounting evidence indicates the novel role of the mineralocorticoid system in cardiometabolic health with excess mineralocorticoid system activity being associated with adiposity, diabetes, insulin resistance and cardiovascular diseases independent of its effect on BP, and RAAS blockade and MR antagonists offering protection against cardiometabolic dysfunction. The metabolic manifestations of mineralocorticoid system overactivation are mainly mediated by their interactions with adipose tissue which orchestrates energy, lipids and glucose homeostasis via effects on the functions of brown and white adipocytes and immune cells. Adipose tissue can in turn influence mineralocorticoid system activity by harbouring its own RAAS system and by releasing mineralocorticoid-secretory factors/adipokines, with resultant further progression of cardiometabolic dysfunction. This article discusses the interplay between the mineralocorticoid system and adipose tissue in the pathophysiology of cardiometabolic diseases.

Untangling the Uncertain Role of Overactivation of the Renin-Angiotensin-Aldosterone System with the Aging Process Based on Sodium Wasting Human Models.

Every individual at some point encounters the progressive biological process of aging, which is considered one of the major risk factors for common diseases. The main drivers of aging are oxidative stress, senescence, and reactive oxygen species (ROS). The renin-angiotensin-aldosterone system (RAAS) includes several systematic processes for the regulation of blood pressure, which is caused by an imbalance of electrolytes. During activation of the RAAS, binding of angiotensin II (ANG II) to angiotensin II type 1 receptor (AGTR1) activates intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate superoxide anions and promote uncoupling of endothelial nitric oxide (NO) synthase, which in turn decreases NO availability and increases ROS production. Promoting oxidative stress and DNA damage mediated by ANG II is tightly regulated. Individuals with sodium deficiency-associated diseases such as Gitelman syndrome (GS) and Bartter syndrome (BS) show downregulation of inflammation-related processes and have reduced oxidative stress and ROS. Additionally, the histone deacetylase sirtuin-1 (SIRT1) has a significant impact on the aging process, with reduced activity with age. However, GS/BS patients generally sustain higher levels of sirtuin-1 (SIRT1) activity than age-matched healthy individuals. SIRT1 expression in GS/BS patients tends to be higher than in healthy age-matched individuals; therefore, it can be assumed that there will be a trend towards healthy aging in these patients. In this review, we highlight the importance of the hallmarks of aging, inflammation, and the RAAS system in GS/BS patients and how this might impact healthy aging. We further propose future research directions for studying the etiology of GS/BS at the molecular level using patient-derived renal stem cells and induced pluripotent stem cells.

State of the art on angiotensin-neprilysin inhibitors.

Angiotensin receptor neprilysin inhibitor (ARNI) decreases renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous systems (SNS) activity promoting vasodilation, decreasing myocardial hypertrophy and fibrosis. Beyond the SNS, RAAS and natriuretic peptide systems, ARNI results in increased circulatory and myocardial nitric oxide levels activating cGMP and protein kinase G, which reduces oxidative stress, myocyte hypertrophy, cell death and has anti-thrombotic effects. ARNIs have a class I indication by heart failure (HF) guidelines in HFrEF patients with NYHA class II to III symptoms. Beyond HFrEF, the use of ARNIs has also been expanded to other clinical settings including HF with preserved ejection fraction (EF, HFpEF), acute HF, advanced HF, hypertension, arrhythmias and chronic kidney disease. This paper reviews the clinical benefits of ARNIs in both HF and the aforementioned cardiovascular conditions. We also discuss the combined use of ARNI with SGLT2i and their potential synergistic benefits on cardiovascular outcomes.

Abstract 17: SARS-CoV-2 Spike Protein Exacerbates Thromboembolic Cerebrovascular Complications in Humanized ACE2 Mouse Model

COVID-19 doubles the risk for acute ischemic stroke in patients with cardiovascular disorders, yet, the molecular mechanisms are unclear and remain unresolved medical challenges. We hypothesize that SARS-CoV-2 spike protein exacerbates stroke and neurovascular complications via increasing coagulation and decreasing fibrinolysis by disrupting the renin-angiotensin-aldosterone system (RAAS) balance. Methods: MCA/FeCl 3 thromboembolic model was induced in humanized ACE2 knock-in mice. hACE2 mice were treated with Losartan, an angiotensin receptor blocker, after one day of SARS-CoV-2 spike protein injection. Cerebral blood flow was measured using a Laser speckle imager. Infarct size was compared using TTC stain. Vascular-induced cognitive function and dementia (VCID) were assessed using a Novel object recognition test. D-dimmer, Tissue factor -3 (TF-3), and Plasminogen activator inhibitor-1 (PAI-1) were measured using ELISA and Western blot to assess coagulation and fibrinolysis. Human brain microvascular endothelial cells (HBMEC) were exposed to hypoxia with/without SARS-Co-V2 spike protein and were assessed for coagulation factors, inflammation, and RAAS balance. Results: SARS-CoV-2 spike protein increased neuronal death and decreased cognitive function after MCA/FeCl 3 thromboembolic occlusion. hACE2 mice subjected to SARS-CoV-2 spike protein showed diminished cerebral blood flow compared to control groups. SARS-CoV-2 spike protein increased coagulation factors (increased TF-3, P<0.05) and decreased fibrinolysis (increased PAI-1, P<0.05) in hACE2 and HBMVEC. Losartan reduced spike protein-induced infarction and improved cognitive function in hACE2 mice. SARS-CoV-2 spike protein caused RAAS system imbalances in hACE2 mice by increasing AT 1 R and downstream inflammatory signal. Moreover, spike protein decreased the protective RAAS arm by decreasing AT 2 R and Mas receptors in hACE2 mice and HBMVEC. Conclusion: SARS-CoV-2 spike protein exacerbates hypercoagulation and inflammation leading to increased cerebrovascular damage and cognitive dysfunction. However, the AT 1 R blocker, Losartan, restored the RAAS balance and reduced COVID-19-induced thromboembolic cerebrovascular complications.

The RAAS system SNPs polymorphism is associated with essential hypertension risk in rural areas in northern China.

Objectives: Epidemiological evidence has shown that genetics and environment are associated with the risk of hypertension. However, the specific SNP effects of a cluster of crucial genes in the RAAS system on the risk of hypertension are unclear. Methods: A case-control study was performed on the baseline participants of Environment and Chronic Disease in Rural Areas of Heilongjiang China (ECDRAHC) study. According to the inclusion and exclusion criteria, 757 subjects (428 hypertensive patients) were enrolled. A total of 32 SNP sites and related haplotypes, involved in AGT (angiotensinogen), ACE (angiotensin-converting enzyme), AGTR1, CYP11B2 (aldosterone-synthase), LDLR (low-density lipoprotein receptor), LRP5 (low-density lipoprotein receptor associated protein 5), LRP6 (low-density lipoprotein receptor associated protein 6), PPARG (peroxisome proliferator-activated receptor gamma) and ACE2 (angiotensin-converting enzyme 2) genes which exert important roles in renin-angiotensin-aldosterone system (RAAS) system were analyzed. Furthermore, a polygenic scoring model was established to assess individual risk of developing hypertension based on the comprehensive SNPs effects in genes related the RAAS system. Results: After controlling the impact of confounding factors, multivariate logistic regression analysis revealed that the distribution of AGT/rs5046, LRP6/rs12823243 and ACE2/rs2285666 was associated with susceptibility to essential hypertension. In genetic score model, the score > -0.225 had a higher risk, the OR (95%CI) was 1.229 (1.110, 1.362). Conclusions: To the best of our knowledge, this is the first time a hypertension risk scoring model on RAAS associated gene cluster has been constructed, which will provide a novel approach for prevention and control of essential hypertension.

Serum Soluble Angiotensin-Converting Enzyme-2 Level and Its Potential Association With The Renin-Angiotensin-Aldosterone System in Non-Hypertensive Iraqi COVID-19 Patients: An Observational Study

Background: The novel coronavirus disease (COVID-19) is caused by Severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) which utilizes angiotensin converting enzyme2 (ACE2) to invade the host cells. This membrane-bound peptidase is widely distributed in the body; its activity antagonizes the renin-angiotensin-aldosterone system (RAAS). Once SARS-Cov2 enters the cell, it causes downregulation of ACE2, resulting in the unopposed activation of RAAS. The unregulated activity of the RAAS system can deteriorate the prognosis in COVID-19 patients. A soluble form of ACE2 (sACE2) was reported to have a role in the SARS-Cov2 invasion of the susceptible cells.
 Aim of the study: This study aims to investigate the potential association of serum levels of sACE2 and RAAS components in severe COVID-19 patients compared to healthy individuals.
 Methods: Eighty-five participants enrolled in the study were grouped into 45 non-hypertensive severe COVID-19 patients and 40 healthy individuals with comparable age and gender. Serum levels of sACE2, renin, angiotensin 2, and aldosterone by ELISA, and serum potassium level was measured by turbidimetric method.
 Results: The results showed a significant difference in the serum levels of sACE2 (lower), renin, angiotensin 2, and aldosterone (higher) in COVID-19 patients compared to the control subjects (p-value <0.001; for all.
 Conclusion: Non-hypertensive severe COVID-19 patients have lower sACE2 and higher RAAS peptide levels, and they can serve as diagnostic markers of severe COVID-19 patients.
 Recommendations: we recommend a future study with a larger sample size that enrolls COVID-19 patients with different severity levels.
 Keywords: Aldosterone, Angiotensin, COVID-19, Renin, Soluble angiotensin converting enzyme 2

FRI153 Genetic Variant In Armadillo Repeat Containing 5 Gene (ARMC5) Associates With Salt Sensitivity Of Blood Pressure And Aldosterone In A Caucasian Cohort

Abstract Disclosure: W.W. Parksook: None. M. Heydarpour: None. L. Pojoga: None. A. Gaye: None. G.H. Gibbons: None. G.H. Williams: Advisory Board Member; Self; Cereno. Consulting Fee; Self; Alnylam, Crinetics, Damian, KBP bioscience, Paxel, Relapsa, Unicycive. Grant Recipient; Self; NIH 2 grants. J.S. Williams: Advisory Board Member; Self; Mellicell, Inc. Background: Genetic alterations of ARMC5 have been reported in various adrenal disorders, particularly in primary bilateral macronodular adrenal hyperplasia. Increasing evidence shows that polymorphic variants in ARMC5 are also associated with blood pressure (BP), hypertension, and the renin-angiotensin-aldosterone-system (RAAS) in individuals of African descent; however, little is known about these relationships in Caucasians. Herein, we conducted a deep phenotyping study to assess the association of ARMC5 variants with BP, salt sensitivity of BP (SSBP), and components of the RAAS in Caucasians. Methods: Normotensive and hypertensive, non-diabetic, non-chronic kidney disease, Caucasian participants underwent two dietary interventions at 5-7 days apart (200 mmol/day and 10 mmol/day sodium) to assess SSBP and other hormonal parameters. All participants were genotyped using a Multi-Ethnic-Genotyping-Array. Association analysis and the quality control of the genomic data were assessed by PLINK. Participants with complete data for SSBP and hormonal parameters, who were in salt balance, were included in the analysis (n= 306). Multiple linear regression models were used to assess the association between the genetic variant and outcome parameters. Results: There were 5 single nucleotide polymorphisms in the ARMC5 region. rs4889660 was significantly associated with SSBP in additive and dominant models when adjusted by Bonferroni correction. In a candidate gene analysis, rs4889660 risk allele carriers had greater SSBP than non-risk allele homozygotes (β= 4 mmHg, P= 0.03). Following dietary sodium restriction, rs4889660 risk allele carriers had lower serum aldosterone levels in an upright position (β= -6.9 ng/dl, P= 0.04) and serum aldosterone levels after angiotensin II stimulation (β= -3.0 ng/dl, P= 0.02). There were no differences between plasma renin activity, serum and urinary cortisol levels, and renal plasma flows between genotypes. Conclusions: There was an association between the ARMC5 rs4889660 variant and SSBP in Caucasians. With dietary sodium restriction, aldosterone responses to both upright posture and angiotensin II infusion were lower in the risk allele carriers. The reduced aldosterone responses suggest that an alteration in the RAAS system is not the cause of the SSBP, but is in response to a defect in another sodium-mediated homeostatic mechanism. Presentation: Friday, June 16, 2023

Impact of gut microbiome on the renin-aldosterone system: Shika-machi Super Preventive Health Examination results.

The renin-angiotensin-aldosterone system (RAAS) is a regulatory mechanism of the endocrine system and is associated with various diseases, including hypertension and renal and cardiovascular diseases. The gut microbiota (GM) have been associated with various diseases, mainly in animal models. However, to our knowledge, no studies have examined the relationship between the RAAS and GM in humans. The present study aimed to assess the association between the systemic RAAS and GM genera and their causal relationships. The study participants were 377 members of the general population aged 40 years or older in Shika-machi, Japan. Plasma renin activity (PRA), plasma aldosterone concentration (PAC), aldosterone-renin ratio (ARR), and GM composition were analyzed using the 16S rRNA method. The participants were divided into high and low groups according to the PRA, PAC, and ARR values. U-tests, one-way analysis of covariance, and linear discriminant analysis of effect size were used to identify the important bacterial genera between the two groups, and binary classification modeling using Random Forest was used to calculate the importance of the features. The results showed that Blautia, Bacteroides, Akkermansia, and Bifidobacterium were associated with the RAAS parameters. Causal inference analysis using the linear non-Gaussian acyclic model revealed a causal effect of Blautia on PAC via SBP. These results strengthen the association between the systemic RAAS and GM in humans, and interventions targeting the GM may provide new preventive measures and treatments for hypertension and renal disease.

A PROOF-OF-PRINCIPLE EPIGENOME-WIDE ASSOCIATION STUDY OF PLASMA RENIN AND ALDOSTERONE CONCENTRATION IN A GHANAIAN POPULATION: THE RODAM STUDY

Objective: The epigenetic regulation of the renin-angiotensin-aldosterone system (RAAS) potentially plays a role in the pathophysiology underlying the high burden of hypertension in sub-Saharan Africans (SSA). In this first epigenome-wide association study (EWAS) of plasma renin and aldosterone concentrations, we explored the association between DNA methylation and concentrations of renin and aldosterone. Design and method: Epigenome-wide DNA methylation was measured using the Illumina 450k array on whole blood samples of 68 Ghanaian participants of the Research on Obesity and Diabetes among African Migrants Study (RODAM). Differentially methylated positions (DMPs) were assessed for plasma renin and aldosterone concentration using linear regression models adjusted for age, sex, body mass index, diabetes mellitus, hypertension, and technical covariates. Additionally, we extracted methylation loci previously associated with hypertension, kidney function, or that were annotated to RAAS-related genes, and associated these with renin and aldosterone concentration. Results: We identified one epigenome-wide significant DMP associated with renin, and ten DMPs associated with aldosterone. Top DMPs were annotated to the PTPRN2, SKIL, and KCNT1 genes, which have been reported in relation to cardiometabolic risk factors, atherosclerosis, and sodium-potassium handling. Moreover, EWAS loci previously associated with hypertension, kidney function, or RAAS-related genes, were also associated with renin and aldosterone concentration. Conclusions: In this first EWAS on RAAS hormones, we identified DMPs associated with renin and aldosterone in a SSA population. These findings are a first step in understanding the role of DNA methylation in regulation of the RAAS in general, and in a SSA population specifically. The results of this proof-of-principle study will inform new analyses including a larger sample size and a new methylation array (Illumina Infinium MethylationEPIC), which will we use to replicate these initial findings. This will help to further establish the role of DNA methylation and the RAAS system in the hypertension burden in SSA populations.

Non-Haemodynamic Mechanisms Underlying Hypertension-Associated Damage in Target Kidney Components.

Arterial hypertension (AH) is a global challenge that greatly impacts cardiovascular morbidity and mortality worldwide. AH is a major risk factor for the development and progression of kidney disease. Several antihypertensive treatment options are already available to counteract the progression of kidney disease. Despite the implementation of the clinical use of renin-angiotensin aldosterone system (RAAS) inhibitors, gliflozins, endothelin receptor antagonists, and their combination, the kidney damage associated with AH is far from being resolved. Fortunately, recent studies on the molecular mechanisms of AH-induced kidney damage have identified novel potential therapeutic targets. Several pathophysiologic pathways have been shown to play a key role in AH-induced kidney damage, including inappropriate tissue activation of the RAAS and immunity system, leading to oxidative stress and inflammation. Moreover, the intracellular effects of increased uric acid and cell phenotype transition showed their link with changes in kidney structure in the early phase of AH. Emerging therapies targeting novel disease mechanisms could provide powerful approaches for hypertensive nephropathy management in the future. In this review, we would like to focus on the interactions of pathways linking the molecular consequences of AH to kidney damage, suggesting how old and new therapies could aim to protect the kidney.

Sacubitril/valsartan: research progress of multi-channel therapy for cardiorenal syndrome.

Cardiorenal syndrome (CRS) results from complex interaction between heart and kidneys, inducing simultaneous acute or chronic dysfunction of these organs. Although its incidence rate is increasing with higher mortality in patients, effective clinical treatment drugs are currently not available. The literature suggests that renin-angiotensin-aldosterone system (RAAS) and diuretic natriuretic peptide (NP) system run through CRS. Drugs only targeting the RAAS and NPs systems are not effective. Sacubitril/valsartan contains two agents (sacubitril and valsartan) that can regulate RAAS and NPs simultaneously. In the 2017 American College of Cardiology/American Heart Association/American Heart Failure (HF) ssociation (ACC/AHA/HFSA) guideline, sacubitril/valsartan was recommended as standard therapy for HF patients. The latest research shows that Combined levosimendan and Sacubitril/Valsartan markets are protected the heart and kidney against cardiovascular syndrome in rat. However, fewer studies have reported its therapeutic efficacy in CRS treatment, and their results are inconclusive. Therefore, based on RAAS and NPs as CRS biomarkers, this paper summarizes possible pathophysiological mechanisms and preliminary clinical application effects of sacubitril/valsartan in the prevention and treatment of CRS. This will provide a pharmacological justification for expanding sacubitril/valsartan use to the treatment of CRS.

A New Perspective on the Renin-Angiotensin System

Cardiovascular disease (CVD) is the leading cause of death in the world. Hypertension is a serious medical problem not only in adults but also in children and adolescents. The renin-angiotensin-aldosterone system (RAAS) is one of the most important mechanisms regulating blood pressure and the balance of water and electrolytes. According to the latest reports, RAAS acts not only on endocrine but also on paracrine, autocrine, and intracrine. Moreover, RAAS has a component associated with hypotension and cardioprotective effects. These components are called alternative pathways of RAAS. The most important peptide of the alternative pathway is Ang 1-7, which is related to the Mas receptor. Mas receptors have widely known antihypertension properties, including vasodilatation, the release of nitric oxide, and increased production of anti-inflammatory cytokines. Another interesting peptide is angiotensin A, which combines the properties of the classical and alternative pathways. No less important components of RAAS are the proteolytic enzymes angiotensin convertase enzyme type 1 and 2. They are responsible for the functioning of the RAAS system and are a hypertension therapeutic target. Also involved are tissue-specific enzymes that form a local renin-angiotensin system. Currently, a combination of drugs is used in hypertension treatment. These drugs have many undesirable side effects that cannot always be avoided. For this reason, new treatments are being sought, and the greatest hope comes from the ACE2/ang 1-7/MasR axis.

Angiotensin II type I receptor gene polymorphism in essential hypertensive and normotensive subjects

Hypertension is a polygenic disorder that involves a complex interplay of genetic and environmental factors. Genes that influence the renin–angiotensin–aldosterone system (RAAS) appear to be particularly important among the many potential candidate components of EHT. The RAAS system plays an important role in BP regulation by maintaining vascular tone and renal hemodynamics. Most of these are mediated via the activation of the angiotensin II type 1 receptor (AT1R). Untreated hypertension increases the risk of developing cardiovascular diseases such as stroke, myocardial infarction, ischemic heart disease, and, target organ damage. A polymorphism in the 3’ untranslated region of the AT1R gene has been described with either an adenine (A) or a cytosine (C) base (A/C transversion) at the 1166 position that is associated with increased blood pressure. A total of 170 hypertensive patients and 170 normal subjects were included in the present study. Genomic DNA was isolated from peripheral blood leukocytes, amplified with PCR, and separated with gel electrophoresis to determine the AT1R genotype. On electrophoresis, the genotypes A/A-359 bp, A/C-220+139 bp, and C/C-220, 139, and 359 bp were identified. In hypertensive patients, the CC genotype was present in 21.18 percent (n = 36) as compared to 11.76 percent (n = 20) in non-hypertensive patients. In this study AT1R CC homozygote was significantly associated with hypertension (p = 0.019). The odds ratio related to the association of the prevalence of the CC genotype with hypertension was 2.014 (95% CI: 1.112–3.650).: From the present study, it is concluded that AT1R gene polymorphism is associated with hypertension, and with the CC genotype, the risk of hypertension increases in comparison to AC and AA. A allele is not significantly associated with hypertension, but the recessive and co-dominant modes of inheritance of allele C (CC) and its co-dominant mode (AC) are a genetic predisposition to hypertension.

Variations in Urinary Renin-Angiotensin-Aldosterone Component Concentrations in Paediatric IgA Vasculitis Nephritis

IgA Vasculitis (IgAV) is the most common form of vasculitis in children, and 1–2% of patients develop chronic kidney disease. In other forms of glomerulonephritis, there is strong evidence to support the role of the renin-angiotensin-aldosterone system (RAAS); however, data are lacking in IgAV nephritis. This study evaluated urinary RAAS components in children with IgA vasculitis, both with nephritis (IgAVN) and without nephritis (IgAVwoN). Urinary concentrations of renin, angiotensinogen and aldosterone were quantified using ELISAs. In total, 40 patients were included: IgAVN n = 9, IgAVwoN n = 17, HC n = 14, with a mean age of 8.3 ± 3.3 years. Urinary renin demonstrated no trend with nephritis. Urinary angiotensinogen was statistically significantly elevated in IgAV (1.18 ± 1.16 ng/mmol) compared to HC (0.28 ± 0.27 ng/mmol, p = 0.0015), and IgAVN (2.00 ± 1.22 ng/mmol) was elevated compared to IgAVwoN (0.74 ± 0.89 ng/mmol, p = 0.0492) and HC (p = 0.0233). Urinary aldosterone levels were significantly elevated in IgAV (1236 ± 1438 pg/mmol) compared to HC (73.90 ± 65.22 pg/mmol, p < 0.0001); this was most increased in IgAVwoN patients (1793 ± 1507 pg/mmol; IgAVN 183.30 ± 111.30 pg/mmol, p = 0.0035, HC p < 0.0001). As expected, the RAAS system is activated in patients with IgAVN and, more surprisingly, even in those without active nephritis. Further studies are needed to fully understand the role of the RAAS system in IgA vasculitis.

Current options for slowing the progression of chronic kidney disease.

From a certain stage, chronic kidney disease progresses to terminal kidney failure that requires renal replacement therapy with dialysis or transplantation. The progression can be significantly slowed by blocking the renin angiotensin aldosterone system (RAAS) with angiotensin converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARB). Another new option to enhance the effect of blocking the RAAS system is the use of sodium glucose cotransporter 2 (SGLT2) inhibitors, or gliflozins. Dapagliflozin is currently available and reimbursed for patients with both diabetic and non-diabetic kidney disease. In the near future, treatment with the mineralocorticoid receptor inhibitor finerenone should be made available that significantly potentiates the effect of ACE or ARB inhibitors. Recent data show that it is possible to influence the progression of renal insufficiency with exercise.

Unravelling the Mechanistic Role of ACE2 and TMPRSS2 in Hypertension: A Risk Factor for COVID-19.

This review explores the mechanistic action of angiotensin-converting enzyme- 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) in the renin-angiotensinaldosterone system (RAAS) that predisposes hypertensive patients to the adverse outcome of severe COVID-19. Entry of SARS-CoV-2 into the host cell via ACE2 disrupts the RAAS system, creating an imbalance between ACE and ACE2, with an increased inflammatory response, leading to hypertension (HTN), pulmonary vasoconstriction and acute respiratory distress. SARSCoV- 2 may also predispose infected individuals with existing HTN to a greater risk of severe COVID-19 complications. In the duality of COVID-19 and HTN, the imbalance of ACE and ACE2 results in an elevation of AngII and a decrease in Ang (1-7), a hyperinflammatory response and endothelial dysfunction. Endothelial dysfunction is the main factor predisposing hypertensive patients to severe COVID-19 and vice-versa. Despite the increase in ACE2 expression in hypertensive SARS-CoV-2 infected patients, ARBs/ACE inhibitors do not influence their severity and clinical outcomes, implicating continued usage. Future large-scale clinical trials are warranted to further elucidate the association between HTN and SARS-CoV-2 infection and the use of ARBs/ACEIs in SARS-CoV-2 hypertensive patients.

A narrative review of Hyporeninemic hypertension-an indicator for monogenic forms of hypertension.

While the role of the renin-angiotensin-aldosterone system (RAAS) in the development of hypertension is well known, the significance and contribution of low renin hypertension is often overlooked. RAAS stimulation results in more tubular absorption of sodium and water along the nephron, contributing to a higher circulating vascular volume. In addition, members of the RAAS system, such as angiotensin II, have direct effects on vascular vasoconstriction, the heart, aldosterone synthesis in the adrenal glands, the sympathetic nervous system, and the central nervous system. This has resulted in a line of antihypertensive therapeutics targeting RAAS with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and renin inhibitors, which prevent conversion of angiotensinogen to angiotensin. While general practitioners and nephrologists are well aware of the causes and the long-term consequences of elevated renin and aldosterone levels, the opposite situation with low renin and/or low aldosterone levels is frequently underappreciated. The objective of this review is to provide insight to the less common forms of hyporeninemic hypertension. We searched the PubMed online library for keywords related to hyporeninemic hypertension and focused on the pediatric population. For pathophysiology we focused on literature of the last 5 years. The low renin and aldosterone levels may be indicators of inherited (especially when associated with hypokalemia), monogenic forms of hypertension stimulating excessive tubular sodium and water absorption which subsequently results in plasma volume expansion and hypertension. These forms of hypertension require frequently specific forms of therapy. This underlines the importance of the practitioner to be familiar with these rare diseases. In this review article, we outline the different forms of hypertension characterized by low renin/low aldosterone and low renin/high aldosterone levels, how to diagnose these forms of hypertension, and how to treat them.

IN SILICO IDENTIFICATION TESTING OF TRITERPENE SAPONINES ON CENTELLA ASIATICA ON INHIBITOR RENIN ACTIVITY ANTIHYPERTENSIVE

The renin-angiotensin-aldosterone system (RAAS) has an essential role in the occurrence of hypertension. Two drugs that act on SRAA are ACE Inhibitor and ARB. ACE inhibitor and ARB are two antihypertensive drugs that act on RAAS. However, both drugs are not fully effective because they produce incomplete suppression of RAAS. The therapeutic potential of the two drugs is limited, so it is necessary to find out other drugs that are more effective in inhibiting the RAAS system. Renin-inhibitors are evolving as options that can inhibit at the highest levels in RAAS. Discontinuation of renin inhibitor therapy does not cause rebound hypertension as in ACEIs and ARBs. The search for natural renin inhibitors began to be carried out as an alternative to aliskiren. Renin-inhibitors derived from natural ingredients generally come from the class of saponin compounds or polyphenol compounds. One of Indonesia's native plants that contain saponins and polyphenols is Centella asiatica. Thus, research on the antihypertensive potential of these plants was carried out. It is expected that the Centella asiatica plant has a renin inhibitor effect as a blood pressure-lowering drug derived from herbs but has the same effect as aliskiren. The research method was carried out in silico to test the activity of compounds that have potential as antihypertensives in the Centella asiatica plant. The method used is molecular docking, with the docking software used being Molegro Virtual Docker (MVD) 6.0. The results showed that madecasoside and asiaticoside from the Centella asiatica plant have intense renin inhibitor activity, with a mean re-rank score of-105.27 and-93.67, respectively. The conclusion is that madecasoside has similarities with aliskiren with a re-rank value of-105.27. The smallest re-rank value indicates the similarity and strong protein binding between the tested ligand compound and the comparison protein.

The effect of renin-angiotensin-aldosterone system blockers on the course of COVID-19 in patients with arterial hypertension

Objective. To determine the presence or absence of the effect of therapy with renin-angiotensin-aldosterone system (RAAS) blockers in patients with COVID-19.Design and methods. We examined 57 patients who were treated in a medical unit at the FGAU CEC “Patriot” in the period from October to November 2020, with the diagnosis of “New coronavirus infection” and differed in the prescribed antihypertensive therapy. In group 1, drugs that affect the RAAS were used to treat hypertension before COVID-19 onset and during the treatment of COVID-19. In group 2, other drugs were used as the main antihypertensive agents before and during treatment for COVID-19. The severity of pneumonia in patients according to the results of computed tomography was 1–2. The patients were monitored for anthropometric indicators, body temperature, and laboratory data.Results. Groups 1 and 2 are comparable, differing only by height, but not by body mass index. The duration of treatment in group 2 was 1–2 days shorter than in group 1, but the result is not statistically significant due to the small sample. Thus, the hypothesis that differences between previous and ongoing antihypertensive therapy throughout the COVID-19 treatment period may affect the course and effectiveness of treatment has not been confirmed.Conclusions. Concomitant antihypertensive therapy with RAAS blockers does not alter the course of COVID-19 infection in patients. The duration of COVID-19 in patients receiving RAAS system blockers may be one day longer than for patients receiving other antihypertensive therapy.