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Advances in Chronic Kidney Disease Sep 2020Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links... (Review)
Review
Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, into host cells. Because RAS inhibitors have been suggested to increase ACE2 expression, health-care providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.
Topics: Acute Lung Injury; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; COVID-19; Comorbidity; Humans; Hypertension; JNK Mitogen-Activated Protein Kinases; Lung; MAP Kinase Signaling System; Peptide Fragments; Protective Factors; Receptors, Coronavirus; Renin-Angiotensin System; Risk Factors; SARS-CoV-2; Up-Regulation
PubMed: 33308506
DOI: 10.1053/j.ackd.2020.07.002 -
Molecular Biology Reports Sep 2021In rheumatoid arthritis (RA) and osteoarthritis (OA), chronic inflammatory processes lead to progresive joint destruction. The renin-angiotensin system (RAS) is involved... (Review)
Review
BACKGROUND
In rheumatoid arthritis (RA) and osteoarthritis (OA), chronic inflammatory processes lead to progresive joint destruction. The renin-angiotensin system (RAS) is involved in the pathogenesis of RA and OA. The aim of this mini-review article is to summarize evidence on the role of RAS in RA and OA.
METHODS
A non-systematic search in Pubmed included terms as "rheumatoid arthritis", "renin angiotensin system", "osteopenia", "RANKL", "DKK-1", "MMP", "inflammation", "angiogenesis", "local renin-angiotensin system", "angiotensin converting enzyme", "AT2 receptor", "Ang-(1-7)", "VEGF", "angiotensine receptor blocker", "angiotensin converting enzyme inhibitors", "renin inhibitors".
RESULTS
Both RAS axes, the classical one, formed by angiotensin converting enzyme (ACE), angiotensin (Ang) II and AT1 receptor (AT1R) and the counter-regulatory one, composed by ACE2, Ang-(1-7) and the Mas receptor, modulate inflammation and tissue damage. Ang II activates pro-inflammatory mediators and oxidative stress. Conversely, Ang-(1-7) exerts anti-inflammatory actions, decreasing cytokine release, leukocyte attraction, density of vessels, tissue damage and fibrosis. Angiogenesis facilitates inflammatory cells invasion, while osteopenia causes joint dysfunction. Up-regulated osteoclastogenisis and down-regulated osteoblastogeneses were associaed with the activation of the classical RAS axis. Three different pathways, RANKL, DKK-1 and MMPs are enhanced by classical RAS activation. The treatment of RA included methotrexate and corticosteroids, which can cause side effects. Studies with angiotensin receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEi) and renin inhibitors have been conducted in experimental and clinical RA with promising results.
CONCLUSION
The classical RAS activation is an important mechanism in RA pathogenesis and the benefit of ARB and ACEi administration should be further investigated.
Topics: Adrenal Cortex Hormones; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Osteoarthritis; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Signal Transduction; Treatment Outcome
PubMed: 34417705
DOI: 10.1007/s11033-021-06672-8 -
Journal of the... 2021Coronavirus disease 2019 (COVID-19) can occur due to contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has no confined treatment and,... (Review)
Review
Coronavirus disease 2019 (COVID-19) can occur due to contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has no confined treatment and, consequently, has high hospitalization and mortality rates. Moreover, people who contract COVID-19 present systemic inflammatory spillover. It is now known that COVID-19 pathogenesis is linked to the renin-angiotensin system (RAS). COVID-19 invades host cells via the angiotensin-converting enzyme 2 (ACE2) receptor-as such, an individual's susceptibility to COVID-19 increases alongside the upregulation of this receptor. COVID-19 has also been associated with interstitial pulmonary fibrosis, which leads to acute respiratory distress, cardiomyopathy, and shock. These outcomes are thought to result from imbalances in angiotensin (Ang) II and Ang-(1-7)/alamandine activity. ACE2, Ang-(1-7), and alamandine have potent anti-inflammatory properties, and some SARS-CoV-2 patients exhibit high levels of ACE2 and Ang-(1-7). This phenomenon could indicate a failing physiological response to prevent or reduce the severity of inflammation-mediated pulmonary injuries. Alamandine, which is another protective component of the RAS, has several health benefits owing to its antithrombogenic, anti-inflammatory, and antifibrotic characteristics. Alamandine alleviates pulmonary fibrosis via the Mas-related G protein-coupled receptor D (MrgD). Thus, a better understanding of this pathway could uncover novel pharmacological strategies for altering proinflammatory environments within the body. Following such strategies could inhibit fibrosis after SARS-CoV-2 infection and, consequently, prevent COVID-19.
Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Antiviral Agents; COVID-19; Humans; Oligopeptides; Peptide Fragments; Renin-Angiotensin System; COVID-19 Drug Treatment
PubMed: 34853605
DOI: 10.1155/2021/6824259 -
Hypertension Research : Official... Aug 2021
Topics: Angiotensin I; Biomarkers; Bradykinin; Humans; Metabolic Syndrome; Peptide Fragments
PubMed: 34045691
DOI: 10.1038/s41440-021-00671-9 -
Molecular and Cellular Endocrinology Jun 2021The observation that all components of the renin angiotensin system (RAS) are expressed in the kidney and the fact that intratubular angiotensin (Ang) II levels greatly... (Review)
Review
The observation that all components of the renin angiotensin system (RAS) are expressed in the kidney and the fact that intratubular angiotensin (Ang) II levels greatly exceed the plasma concentration suggest that the synthesis of renal Ang II occurs independently of the circulating RAS. One of the main components of this so-called intrarenal RAS is angiotensin-converting enzyme (ACE). Although the role of ACE in renal disease is demonstrated by the therapeutic effectiveness of ACE inhibitors in treating several conditions, the exact contribution of intrarenal versus systemic ACE in renal disease remains unknown. Using genetically modified mouse models, our group demonstrated that renal ACE plays a key role in the development of several forms of hypertension. Specifically, although ACE is expressed in different cell types within the kidney, its expression in renal proximal tubular cells is essential for the development of high blood pressure. Besides hypertension, ACE is involved in several other renal diseases such as diabetic kidney disease, or acute kidney injury even when blood pressure is normal. In addition, studies suggest that ACE might mediate at least part of its effect through mechanisms that are independent of the Ang I conversion into Ang II and involve other substrates such as N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), Ang-(1-7), and bradykinin, among others. In this review, we summarize the recent advances in understanding the contribution of intrarenal ACE to different pathological conditions and provide insight into the many roles of ACE besides the well-known synthesis of Ang II.
Topics: Acute Kidney Injury; Angiotensin I; Angiotensin II; Animals; Blood Pressure; Bradykinin; Diabetic Nephropathies; Gene Expression Regulation; Humans; Hypertension; Kidney; Mice; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Signal Transduction; Water-Electrolyte Balance
PubMed: 33781839
DOI: 10.1016/j.mce.2021.111257 -
Peptides Sep 2020A large body of evidence suggests a relationship between depression and coronary heart disease (CHD). Angiotensin-Ⅱ (Ang-Ⅱ) and angiotensin-(1-7) [Ang-(1-7)] are...
A large body of evidence suggests a relationship between depression and coronary heart disease (CHD). Angiotensin-Ⅱ (Ang-Ⅱ) and angiotensin-(1-7) [Ang-(1-7)] are considered to exert biological effects in both conditions. Here, we aimed to determine the role of Ang-Ⅱ and Ang-(1-7) in the occurrence of comorbid depression in patients with CHD. Our study included 214 CHD patients and 100 matched healthy controls. Serum Ang-Ⅱ and Ang-(1-7) levels were assessed by ELISA, and the depression symptoms were evaluated by the nine-item Patient Health Questionnaire (PHQ-9). Linear regression and correlation analyses were used to estimate the associations between PHQ-9 scores and Ang-Ⅱ and Ang-(1-7) serum levels. Six single-nucleotide polymorphisms (SNPs) spanning the angiotensin converting enzyme 2 (ACE2) and MAS1 genes were genotyped. The associations between SNPs and depression risk in CHD patients were examined using logistic regression analysis with adjustment for age and gender. Decreased Ang-(1-7) (P < 0.05) and an elevated Ang-Ⅱ/Ang-(1-7) ratio (P < 0.01) were observed in CHD patients with depression compared to CHD patients without depression. PHQ-9 scores were negatively correlated with Ang-(1-7) level (r=-0.44, P < 0.01) and positively correlated with the Ang-Ⅱ/Ang-(1-7) ratio (r = 0.33, P < 0.05). Furthermore, carriers of risk allele T for CHD with depression had significantly higher PHQ-9 scores (P < 0.05), lower Ang-(1-7) level (P < 0.01), and higher Ang-Ⅱ/Ang-(1-7) ratio (P < 0.05) than those CC carriers. Collectively, our results firstly showed that Ang-(1-7) serum level in CHD patients may protect against comorbid depression. Moreover, the imbalance between Ang-Ⅱ and Ang-(1-7) may contribute to depression in CHD patients.
Topics: Adult; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Case-Control Studies; China; Comorbidity; Coronary Disease; Depression; Female; Gene Expression Regulation; Genotype; Humans; Linear Models; Male; Middle Aged; Peptide Fragments; Polymorphism, Single Nucleotide; Proto-Oncogene Mas; Proto-Oncogene Proteins; ROC Curve; Receptors, G-Protein-Coupled; Signal Transduction; Surveys and Questionnaires
PubMed: 32599080
DOI: 10.1016/j.peptides.2020.170353 -
Frontiers in Nutrition 2022Angiotensin-I converting enzyme (ACE) inhibitory peptides drew wide attention in the food industry because of their natural reliability, non-toxicity, and safety....
Angiotensin-I converting enzyme (ACE) inhibitory peptides drew wide attention in the food industry because of their natural reliability, non-toxicity, and safety. However, the characteristics of ACE inhibitory peptides obtained from protein hydrolysate of mulberry leaf prepared by Flavourzyme were still unclear. Based on the single-factor test, the Plackett-Burman test and response surface test were used to determine the key factors affecting the ACE inhibition rate in mulberry leaf protein hydrolysate and the optimum conditions of enzymatic hydrolysis. The results showed that the optimum technical parameters were as follows: the ratio of material to liquid is 1: 25 (w / v, g/mL), the Flavourzyme to substrate ratio was 3,000 U/g, the temperature of enzymatic hydrolysis was 50°C, pH was 6.3, and the time of enzymatic hydrolysis was 2.9 h. The ACE inhibitory peptides in the mulberry leaf protein hydrolysates were purified by ultrafiltration and gel filtration, aiming to obtain the highest active component. The 12 peptide sequences were identified by reverse liquid chromatography-mass spectrometry, and then, they were docked to the crystal structure of human angiotensin-I converting enzyme (1O8A), and the interaction mechanisms of 12 peptide sequences and 1O8A were analyzed. The docking results showed that among the 12 peptide sequences, ERFNVE (792.37 Da), TELVLK (351.72 Da), MELVLK (366.72 Da), and FDDKLD (376.67 Da), all had the lowest docking energy, and inhibition constant. The chemosynthetic ERFNVE (IC: 2.65 mg/mL), TELVLK (IC: 0.98 mg/mL), MELVLK (IC:1.90 mg/mL) and FDDKLD (IC:0.70 mg/mL) demonstrated high ACE-inhibitory activity with competitive inhibition mode. These results indicated that the ACE-inhibiting peptides from mulberry leaf protein hydrolyzed (FHMP) had the potential activities to inhibit ACE and could be used as functional food or drugs to inhibit ACE. This work provides positive support for mining the biological activity of mulberry leaves in the treatment of hypertension.
PubMed: 36825069
DOI: 10.3389/fnut.2022.1064526 -
Journal of the American College of... Apr 2021The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS...
BACKGROUND
The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy.
OBJECTIVES
This study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy.
METHODS
Fifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients.
RESULTS
AngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p < 0.001; and AngIII: 87.4 [IQR: 46.5 to 165.3] fmol/g vs 23.0 [IQR: <5.0 to 59.3] fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity.
CONCLUSIONS
The failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions.
Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Disease Progression; Female; Heart Failure; Heart Transplantation; Humans; Male; Mass Spectrometry; Middle Aged; Myocardium; Peptide Fragments; Renin-Angiotensin System; Stroke Volume
PubMed: 33832600
DOI: 10.1016/j.jacc.2021.01.052 -
Current Drug Targets 2020Pediatric tumors remain the highest cause of death in developed countries. Research on novel therapeutic strategies with lesser side effects is of utmost importance. In... (Review)
Review
BACKGROUND
Pediatric tumors remain the highest cause of death in developed countries. Research on novel therapeutic strategies with lesser side effects is of utmost importance. In this scenario, the role of Renin-Angiotensin System (RAS) axes, the classical one formed by angiotensinconverting enzyme (ACE), Angiotensin II and AT1 receptor and the alternative axis composed by ACE2, Angiotensin-(1-7) and Mas receptor, have been investigated in cancer.
OBJECTIVE
This review aimed to summarize the pathophysiological role of RAS in cancer, evidence for anti-tumor effects of ACE2/Angiotensin-(1-7)/Mas receptor axis and future therapeutic perspectives for pediatric cancer.
METHODS
Pubmed, Scopus and Scielo were searched in regard to RAS molecules in human cancer and pediatric patients. The search terms were "RAS", "ACE", "Angiotensin-(1-7)", "ACE2", "Angiotensin II", "AT1 receptor", "Mas receptor", "Pediatric", "Cancer".
RESULTS
Experimental studies have shown that Angiotensin-(1-7) inhibits the growth of tumor cells and reduces local inflammation and angiogenesis in several types of cancer. Clinical trials with Angiotensin-( 1-7) or TXA127, a pharmaceutical grade formulation of the naturally occurring peptide, have reported promising findings, but not enough to recommend medical use in human cancer. In regard to pediatric cancer, only three articles that marginally investigated RAS components were found and none of them evaluated molecules of the alternative RAS axis.
CONCLUSION
Despite the potential applicability of Angiotensin-(1-7) in pediatric tumors, the role of this molecule was never tested. Further clinical trials are necessary, also including pediatric patients, to confirm safety and efficiency and to define therapeutic targets.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Child; Humans; Neoplasms; Pediatrics; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System
PubMed: 32039680
DOI: 10.2174/1389450121666200210124217 -
Molecular and Cellular Endocrinology Jun 2021Pregnancy demands major cardiovascular, renal and endocrine changes to provide an adequate blood supply for the growing fetus. The renin-angiotensin-aldosterone system... (Review)
Review
Pregnancy demands major cardiovascular, renal and endocrine changes to provide an adequate blood supply for the growing fetus. The renin-angiotensin-aldosterone system plays a key role in this adaptation process. One of its components, prorenin, is released in significant amounts from the ovary and uteroplacental unit. This review describes the sources of prorenin in the periconception period and in pregnancy, including its modulation by in-vitro fertilization protocols, and discusses its potential effects, among others focusing on preeclampsia. It ends with discussing the long-term consequences, even in later life, of inappropriate renin-angiotensin-aldosterone system activity in pregnancy and offers directions for future research. Ultimately, a full understanding of the role of prorenin periconceptionally and during pregnancy will help to develop tools to diagnose and/or prevent reproductive complications.
Topics: Angiotensin I; Angiotensinogen; Female; Fertilization in Vitro; Gene Expression Regulation; Humans; Ovary; Placenta; Pre-Eclampsia; Pregnancy; Renin; Renin-Angiotensin System; Signal Transduction; Uterus
PubMed: 33878417
DOI: 10.1016/j.mce.2021.111281