Role Of Renin-angiotensin-aldosterone System Research Articles

Angiotensin-(3-4) modulates the overweight- and undernutrition-induced ACE2 downregulation in renal proximal tubule cells: implications for COVID-19?

Aim: The renal lesions–including severe acute kidney injury–are severe outcomes in severe acute respiratory syndrome coronavirus 2 infections. There are no reports regarding the influence of the nutritional status on the severity and progress of these lesions. Ageing is also an important risk factor. Methods: In the present study we compared the influence of overweight and undernutrition on the levels of renal angiotensin converting enzymes 1 and 2 (ACE and ACE2), which were evaluated by Western blotting. Since the renin-angiotensin-aldosterone system (RAAS) has been implicated in the progress of kidney failure during coronavirus disease 2019, the influence of Angiotensin-(3-4) [Ang-(3-4)] was investigated. Ang-(3-4) is the shortest angiotensin-derived peptide, which is considered the physiological antagonist of several Ang II effects. Results: Both overweight and undernutrition downregulate the levels of ACE2 without influence on the levels of ACE in proximal tubules from kidney rats. Administration of Ang-(3-4) upregulates ACE2 to levels above the control in overweight but not in undernourished rats. Conclusions: Chronic undernourishment and overnourishment conditions play a central role in the renal ACE/ACE2 balance, and that the role of RAAS is also different in overweight and undernutrition.

The Role of Renin-Angiotensin-Aldosterone System in the Heart and Lung: Focus on COVID-19

The renin-angiotensin-aldosterone system (RAAS) firstly considered as a cardiovascular circulating hormonal system, it is now accepted as a local tissue system that works synergistically or independently with the circulating one. Evidence states that tissue RAAS locally generates mediators with regulatory homeostatic functions, thus contributing, at some extent, to organ dysfunction or disease. Specifically, RAAS can be divided into the traditional RAAS pathway (or classic RAAS) mediated by angiotensin II (AII), and the non-classic RAAS pathway mediated by angiotensin 1–7. Both pathways operate in the heart and lung. In the heart, the classic RAAS plays a role in both hemodynamics and tissue remodeling associated with cardiomyocyte and endothelial dysfunction, leading to progressive functional impairment. Moreover, the local classic RAAS may predispose the onset of atrial fibrillation through different biological mechanisms involving inflammation, accumulation of epicardial adipose tissue, and electrical cardiac remodeling. In the lung, the classic RAAS regulates cell proliferation, immune-inflammatory response, hypoxia, and angiogenesis, contributing to lung injury and different pulmonary diseases (including COVID-19). Instead, the local non-classic RAAS counteracts the classic RAAS effects exerting a protective action on both heart and lung. Moreover, the non-classic RAAS, through the angiotensin-converting enzyme 2 (ACE2), mediates the entry of the etiological agent of COVID-19 (SARS-CoV-2) into cells. This may cause a reduction in ACE2 and an imbalance between angiotensins in favor of AII that may be responsible for the lung and heart damage. Drugs blocking the classic RAAS (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) are well known to exert a cardiovascular benefit. They are recently under evaluation for COVID-19 for their ability to block AII-induced lung injury altogether with drugs stimulating the non-classic RAAS. Herein, we discuss the available evidence on the role of RAAS in the heart and lung, summarizing all clinical data related to the use of drugs acting either by blocking the classic RAAS or stimulating the non-classic RAAS.

The Role of Angiotensin Antagonism in Coronary Plaque Regression: Insights from the Glagovian Model.

The benefit of antagonizing the effect of the renin angiotensin aldosterone system (RAAS), notably by the use of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor blocker (ARB) for coronary artery disease (CAD), has been demonstrated in multiple studies, which may be attributed to their ability to inhibit the deleterious effect of RAAS to the cardiovascular system. It is well known that angiotensin II (Ang II) plays a vital role in atheromatous plaque formation and progression through multiple pathways, including inflammatory and arterial remodeling aspects. Significant coronary atheromatous plaque regression has been previously demonstrated in various studies using statin agents. Similar results have been reported in different studies using angiotensin inhibitor agents, notably ARB agents. Analysis from various trials utilizing ARB showed a significant plaque regression using olmesartan and telmisartan as evaluated by IVUS studies. In contrary, the use of ACEi did not demonstrated significant plaque regression, which may be attributed to the heavy plaque calcification in respective studies. On this review, we aim to present the basic mechanism on the role of RAAS in plaque modulation and its arterial remodeling aspect, which is then integrated with the clinical evidence based on the available intravascular ultrasonography (IVUS) studies on coronary arteries.

The effect of the components of the renin-angiotensinaldosterone system on the development of diabetic nephropathy in type 1 diabetes (review)

One of the key roles in the development of diabetic nephropathy belongs to the renin-angiotensin-aldosterone system (RAAS), which is involved in the regulation of hemodynamics, systemic and intrarenal pressure, production of profibrogenic and growth factors, vascular remodeling. At the end of the twentieth century, local (tissue) RAAS elements from renin to aldosterone were found in tissues and target organs (including kidneys). Tissue RAAS plays a leading role in the development of vascular complications of diabetes mellitus (DM): cardiovascular disease, diabetic nephropathy, and retinopathy. It is this fact that explains in many ways the pathogenetic role of RAAS in the defeat of target organs even with normal or low plasma renin activity (ARP). RAAS activation occurs long before the clinical signs of diabetic nephropathy, which makes it possible for earlier prevention and correction of initial changes in the study of its components, as well as reducing disability and the output of patients in chronic kidney disease. Given the tendency to “rejuvenate” diabetes mellitus, the lability of the course of the disease in childhood, the high hormonal activity in this group of patients, and, therefore, the greater the risk of complications, the timely diagnosis of the initial manifestations of DN is of high relevance and relevance.

Renin Angiotensin Axis, Angiotensin Converting Enzyme 2 and Coronavirus

The renin-angiotensin-aldosterone system (RAAS) is the main plasma volume regulator, which maintains cardiovascular and hydrosaline homeostasis. In the classical pathway, the angiotensin converting enzyme (ACE) generates Angiotensin II (AngII), which is powerfully inflammatory and vasoconstrictive. This classical pathway is also regulated by ACE2, which converts AngI to Ang 1-9, and degrades AngII to Ang 1-7, whose vasodilatory and anti-inflammatory functions balance out the effects of AngII. ACE2 has been associated with the pathogenesis of respiratory infections such as RSV and severe acute respiratory syndrome coronavirus (SARS-CoV and SARS-CoV-2). Recent studies have shown that ACE2 corresponds to the main SARS-CoV-2 receptor, which together with other receptors such as the TMPRSS2, allows the virus to attach, fuse, and enter the host cell. These studies have shown that in animals infected with coronavirus there is a drop in tissue concentration of ACE2 and Ang 1-7, leading to overexpression of AngII and its vasoconstrictive and inflammatory effects. Experiments with recombinant ACE2 have shown a protective effect against overexpression of RAAS in coronavirus-infected animals, which is similar to that demonstrated with the use of AngII receptor blockers (AT1). Evidence on the protective role of ACE2 seems to support the recommendations re garding not discontinuing these drugs in COVID-19 infection. In this article, we present the current knowledge about the role of RAAS in coronavirus infection, based on physiopathological concepts, molecular bases, and experimental and clinical evidence.

The renin-angiotensin-aldosterone system as a potential target for therapy in patients with calcific aortic stenosis: a literature review

Calcific aortic valve stenosis (CAVS) is a serious socio-economic problem in developed countries because this disease is the most common indication for aortic valve replacement. Currently, there are no methods for non-invasive treatment of CAVS. Nevertheless, it is assumed that effective drug therapy for CAVS can be developed on the basis of modulators of the renin-angiotensin-aldosterone system (RAAS), which is involved in the pathogenesis of this disease. The purpose of this paper is to compile and analyze current information on the role of RAAS in the CAVS pathophysiology. Recent data on the effectiveness of RAAS inhibition are reviewed.

Myocardial fibrosis and atrial fibrillation

Atrial fibrillation is the most prevalent arrhythmia, and tends to progress. Any structural changes in the heart may lead to its progressive remodelling with increased deposition of connective tissue and fibrosis. Predominance of collagen types I and III synthesis over its degradation leads to accumulation of fibers and to fibrosis. Increase of atrial fibrosis is usually found on autopsy and biopsy. There is relation revealed, of atrial fibrosis grade and postsurgery atrial fibrillation. The mechanisms participating in the structural remodelling and progression of atrial fibrosis are not studied well enough, but there is known role of renin-angiotensinaldosterone system, transforming growth factor, inflammation and matrix metalloproteases. As an alternative, one should consider non-invasive diagnostic methods: magnetic resonance imaging of the heart and biomarkers level measurement. Hyperactivation of the renin-angiotensin-aldosterone system facilitates structural remodelling of the heart and progression of atrial fibrosis. Hyperexpression of the transforming growth factor leads to selective atrial fibrosis, heterogeneity of excitation conduction and fibrillation onset. Matrix metalloproteases are the marker of extracellular degradation. Study of fibrosis biomarkers makes it to increase significantly the efficacy of atrial fibrillation course prediction.

Angiotensin converting enzyme activity in alopecia areata.

Background. Alopecia areata (AA) is a chronic inflammatory disease of the hair follicle. The exact pathogenesis of AA remains unknown, although recent studies support a T-cell mediated autoimmune process. On the other hand, some studies have proposed that the renin-angiotensin-aldosterone system (RAAS) may play a role in autoimmunity. Therefore, we assessed serum activity of angiotensin converting enzyme (ACE), a component of this system, in AA. Methods. ACE activity was measured in the sera of 19 patients with AA and 16 healthy control subjects. In addition, the relationship between severity and duration of the disease and ACE activity was evaluated. Results. Serum ACE activity was higher in the patient group (55.81 U/L) compared to the control group (46.41 U/L), but the difference was not statistically significant (P = 0.085). Also, there was no correlation between ACE activity and severity (P = 0.13) and duration of disease (P = 0.25) in the patient group. Conclusion. The increased serum ACE activity found in this study may demonstrate local involvement of the RAAS in the pathogenesis of AA. Assessment of ACE in a study with a larger sample size as well as in tissue samples is recommended in order to further evaluate the possible role of RAAS in AA.

Renin-angiotensin-aldosterone system in hypertrophic cardiomyopathy

Keeping in mind an important role of renin-angiotensin aldosterone system (RAS) in developing of cardiac remodeling and fibrosis, genetic polymorphisms coding its components could have influence with clinical variants of the course. Biomarkers could appear predictors of adverse. To examine the contribution of the RAS to developing of different hypertrophic cardiomyopathy (HCM) clinical variants of the course we studied 58 patients with HCM and controls comparable by age and gender. All patients were genotyped of gene polymorphisms CMA1 A(-1903)G rs1800875, AGTM235T rs699, AGTR1 A1166C rs5186, CYP11B2-344 T/C rs1799998. Angiotensin-converting enzyme (ACE) and angiotensin II (AII) levels were measured in 40 patients with HCM and 39 controls. We found out that AII were significantly decreased in patients with HCM than in healthy controls. The positive correlation between AII and left ventricle posterior wall (LVPW) were detected. Severity of heart hypertrophy were associated with pejorative genotype of AGT M235T polymorphism and CMA1 A(-1903) polymorphism. Significant association between the AG genotype of CMA1 A(-1903) polymorphism and angina class II-III and ventricular extrasystole of high gradation was observed. Our data not only support the hypothesis that RAAS polymorphisms may influence phenotype, but also allow for create new approaches to possible predicting adverse outcomes.

Anti-Vascular Endothelial Growth Factor Therapies and Cardiovascular Toxicity: What Are the Important Clinical Markers to Target?

Therapies targeting vascular endothelial growth factor (VEGF) are associated with hypertension, cardiotoxicity, and thromboembolic events. All prospective phase I-III clinical trials published up to December 2008 of approved anti-VEGF therapies (bevacizumab, sunitinib, sorafenib) and relevant literature were reviewed. The rates of Common Toxicity Criteria (version 3) grade 3-4 hypertension with bevacizumab, sunitinib, and sorafenib were 9.2%, 6.9%, and 7.2%, respectively. Grade 3-4 left ventricular systolic dysfunction was noted in 0.3%, 1.4%, and 0.05% of patients, respectively, whereas the rates of grade 3-4 thromboembolism were 9.6%, 1.2%, and 3.8%, respectively. The renin-angiotensin-aldosterone system (RAAS) may play a key role in vasoconstriction and capillary rarefaction, which are unleashed when VEGF signaling is targeted. Inhibiting RAAS may be the optimal approach for managing these toxicities. In anticipation of cardiovascular complications with anti-VEGF therapies, early detection and personalized management may improve clinical outcomes and tolerance.

Hypertension and Diabetes: Emphasis on the Renin – Angiotensin System and Insulin Resistance

Type 2 Diabetes Mellitus (T2DM) and hypertension (HTN) both increase cardiovascular disease (CVD) morbidity and mortality, and impose a tremendous burden on worldwide heath care systems in recent years. The mechanisms underlying the frequent coexistence of T2DM and HTN, two main components of the Cardiometabolic Syndrome (CMS), remain to be fully uncovered. Interestingly, both conditions are linked by chronic inflammatory processes and insulin resistance that are instigated by enhanced activation of the Renin Angiotensin Aldosterone System (RAAS). Inappropriate activation of the RAAS and insulin resistance with compensatory hyperinsulinemia trigger numerous pathophysiological pathways that ultimately result in endothelial dysfunction, inflammation, proliferation, and remodeling in cardiovascular and renal tissue. Blockade of RAAS has proven beneficial in the management of T2DM and HTN as well as associated CVD and chronic kidney diseases. This review focuses on current knowledge about the role of RAAS and insulin resistance and accompanying inflammation and oxidative stress in the pathophysiology that links DM and HTN. Keywords: Diabetes, hypertension, insulin resistance, renin angiotensin aldosterone system

Nephrotic range proteinuria associated with unilateral renal artery stenosis

Sir, Mild proteinuria is often present in patients with renal artery stenosis (RAS) [1]. However, heavy proteinuria is an uncommon finding in this setting, and many of the reported cases are due to bilateral RAS [2]. A 62-year-old Caucasian male was referred to our nephrology service for worsening kidney function. He had a history of coronary artery disease, chronic kidney disease (baseline serum creatinine level of 2–3 mg/dl), and hypertension. For the past few months prior to admission, he had presented with progressive deterioration in kidney function associated with refractory hypertension. At the time of admission, he had bilateral lower extremity edema with a creatinine of 4.4 mg/dl, proteinuria of 15 g/24 h, and was treated with six antihypertensive medications. Further investigations including immunologic studies and renal ultrasound were normal, except for a plasma renin activity of 11 ng/ml/h (normal: 1–3.8) and an aldosterone level of 35 ng/dl (normal: 1–14). A carbon dioxide angiogram revealed severe ostial right RAS with normal left renal artery. A stent was placed at the site of stenosis with subsequent improvement in renal perfusion. Over the next 2 weeks, the kidney function returned to its baseline (creatinine 3.1 mg/dl), blood pressure was better controlled (needing only one antihypertensive agent), and proteinuria decreased to 2.3 g/24 h. Although mild-to-moderate proteinuria is commonly seen in patients with RAS, massive proteinuria or nephrotic syndrome is considered a rare presentation in this setting. The pathophysiology of this phenomenon is poorly understood, and the main suggested mechanisms are thought to be hormonal and hemodynamic disturbances. The ischemia induced by renal hypoperfusion can result in an increased secretion of renin from the affected kidney. Activation of the renin-angiotensin-aldosterone system (RAAS) is associated with a number of physiologic and pathophysiologic consequences [3]. The role of RAAS in the development of proteinuria was first observed in experimental animals [4] and was then confirmed in human studies. In a study on 96 patients with renal artery occlusion, Rossignol et al. found that the degree of proteinuria was independently related to the active renin level, which reflects plasma angiotensin II concentration. Angiotensin II constricts the efferent arterioles in the unaffected kidney leading to increased intraglomerular pressure [5]. It also acts directly on the endothelial cells resulting in widening of the intra-endothelial gaps and an increase in glomerular capillary permeability [5]. Our patient also showed a high plasma renin activity, likely secondary to RAS. Although biopsy was not done, the significant reduction in the amount of proteinuria over a short period of time supports the hypothesis that the renal hypoperfusion, with A. Wadhwa A. Kazory (&) Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610-0224, USA e-mail: amir.kazory@medicine.ufl.edu

Angiotensin Receptor Blockers and Target-Organ Protection Beyond Blood Pressure Control

The renin-angiotensin-aldosterone system (RAAS) is considered to be the main mediator of the cardiovascular damage associated with high blood pressure. Recent guidelines recognised, both directly and indirectly, the central role of RAAS, reporting the ‘compelling indications’ for the use of drugs that antagonise this system. The results of many large trials with the angiotensin receptor blockers (ARBs) candesartan, losartan, irbesartan and valsartan have been published from the year 2000 to the end of 2003. These trials have been conducted to verify that, beyond blood pressure control, ARBs could offer better organ protection in many different clinical conditions. Despite the favourable premises, some ARB trials not only failed to show superiority, but even equivalence with lower-cost therapies of confirmed efficacy (e.g. captopril 50mg three times daily). On the contrary, other ARB trials (IDNT [Irbesartan Diabetic Nephropathy Trial], IRMA2 [Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria], RENAAL [Reduction of End points in NIDDM with the Angiotensin II Antagonist Losartan], and LIFE [Losartan Intervention for End Point Reduction in Hypertension]) have had such clear-cut outcomes that irbesartan (300mg) and losartan (100mg) are the drugs of choice in type 2 diabetes patients with proteinuria or in hypertensive patients with left ventricular hypertrophy. The key factor for ARBs to succeed in delivering superior organ protection appears to be the high dosages used, dosages uncommonly utilised, with some exceptions, to treat hypertension in clinical practice. The results of the published ARB trials are reviewed, focusing on the dose-efficacy of target-organ protection beyond blood pressure control.