Mas Receptor Research Articles

Effects of exercise training on renal interstitial fibrosis and renin-angiotensin system in rats with chronic renal failure.

To clarify the mechanisms of the renal protective effects of exercise training, we examined the effects of exercise training on the renal interstitial fibrosis and renin-angiotensin system (RAS) in rats with chronic renal failure. Six-week-old male Sprague-Dawley rats were divided into three groups: sham operation; 5/6 nephrectomy + sedentary; 5/6 nephrectomy + exercise training. The 5/6 nephrectomy + exercise training group underwent treadmill running (20 m/min, 60 min/day, 5 days/week). After 12 weeks, renal function, histology and protein expression of collagen type I, transforming growth factor-β1 (TGF-β1), matrix metalloproteinase (MMP), tissue inhibitors of metalloproteinase (TIMP) and RAS components in the renal cortex were examined. Exercise training ameliorated the 5/6 nephrectomy-induced hypertension, proteinuria, renal dysfunction, glomerular sclerosis and renal interstitial fibrosis. 5/6 Nephrectomy increased the expression of collagen type I, TGF-β1, MMP-2, MMP-9, TIMP-1, angiotensinogen, angiotensin-converting enzyme (ACE), (pro)renin receptor and angiotensin II type 1 receptor, and exercise training inhibited the 5/6 nephrectomy-increased expression of collagen type I, TGF-β1, TIMP-1, angiotensinogen and ACE expressions. 5/6 Nephrectomy decreased the expression of renin, ACE2, angiotensin II type 2 receptor and Mas receptor, and exercise training inhibited the 5/6 nephrectomy-decreased expressions. These results indicated that exercise training attenuates the progression of glomerular sclerosis and renal interstitial fibrosis in chronic renal failure rats. The renal protective effects of exercise training may be mediated by ameliorating the renal collagen turnover and the exacerbation of renal RAS.

Obstructive sleep apnea, renin-angiotensin system, and COVID-19: possible interactions.

Citation:Ekiz T, Inonu Koseoglu H, Pazarli AC. Obstructive sleep apnea, renin-angiotensin system, and COVID-19: possible interactions. J Clin Sleep Med. 2020;16(8):1403–1404.

Pathobiological Interactions of Local Bone Marrow Renin-Angiotensin System and Central Nervous System in Systemic Arterial Hypertension.

Circulating renin-angiotensin system (RAS) and local paracrin-autocrin-intracrin tissue-based RAS participate in numerous pathobiological events. Pro-inflammatory, pro-fibrotic, and pro-thrombotic consequences associated with local RAS activation have been detected at cellular and molecular level. Regenerative progenitor cell therapy in response to RAS modulating pharmacotherapy has emerged as an adjunct in the context of endothelial cell injury and regeneration to improve regeneration of the vascular endothelium. Local hematopoietic bone marrow (BM) RAS symbolizes the place of cross-interaction between vascular biology and cellular events from embryogenesis to definitive hematopoiesis underlying vascular atherosclerosis. The BM microenvironment also contains Mas receptors, which control the proliferative role of Ang 1-7 on hematopoietic stem cells. Ang 1-7 is produced from Ang-II or Ang-I with the help of ACE2. Various tissues and organs also have an effect on the RAS system. The leukocytes contain and synthesize immunoreactive angiotensinogen species capable of producing angiotensin in the basal state or after incubation with renin. The significance of RAS employment in atherosclerosis and hypertension was indicated by novel bidirectional Central Nervous System (CNS) RAS–BM RAS communications. Myeloid cells generated within the context of hematopoietic BM RAS are considered as the initiators and decision shapers in atherosclerosis. Macrophages in the atherosclerotic lesions contain angiotensin peptides by which RAS blockers inhibit monocyte activation and adherence. Furthermore, vascular biology in relation to inflammation and neoplasia is also affected by local tissue RAS. The purpose of this article is to outline interactions of circulating and local angiotensin systems, especially local bone marrow RAS, in the vascular pathobiological microenvironment of CNS.

Oestrogen-mediated upregulation of the Mas receptor contributes to sex differences in acute lung injury and lung vascular barrier regulation.

Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; however, sex-dependent incidence of acute respiratory distress syndrome (ARDS) remains controversial and the sex-dependent mechanisms of endothelial barrier regulation are unknown. In premenopausal women, increased signalling of angiotensin (Ang)(1-7) via the Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang(1-7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang(1-7)/Mas signalling may protect females over males in ALI/ARDS.Clinical data were collected from Charité inpatients (Berlin) and sex differences in ALI were assessed in wild-type (WT) and Mas-receptor deficient (Mas-/- ) mice. Endothelial permeability was assessed as weight change in isolated lungs and as transendothelial electrical resistance (TEER) in vitroIn 734 090 Charité inpatients (2005-2016), ARDS had a higher incidence in men as compared to women. In murine ALI, male WT mice had more lung oedema, protein leaks and histological evidence of injury than female WT mice. Lung weight change in response to platelet-activating factor (PAF) was more pronounced in male WT and female Mas-/- mice than in female WT mice, whereas Mas-receptor expression was higher in female WT lungs. Ovariectomy attenuated protection in female WT mice and reduced Mas-receptor expression. Oestrogen increased Mas-receptor expression and attenuated endothelial leakage in response to thrombin in vitro This effect was alleviated by Mas-receptor blockade.Improved lung endothelial barrier function protects female mice from ALI-induced lung oedema. This effect is partially mediated via enhanced Ang(1-7)/Mas signalling as a result of oestrogen-dependent Mas expression.

Baseline use of angiotensin-converting enzyme inhibitor/AT1 blocker and outcomes in hospitalized coronavirus disease 2019 African-American patients.

The primary objective of this study is to determine the effect of baseline use of angiotensin-converting enzyme inhibitor (ACE-i)/AT1 blocker (ARB) on mortality in hospitalized coronavirus disease 2019 (Covid-19) African-American patients. The secondary objectives are, to determine the effect of baseline use of ACE-i/ARB on the need for mechanical ventilation, new dialysis, ICU care, and on composite of above-mentioned outcomes in the same cohort. In this retrospective study, we analyzed data using electronic medical records from all hospitalized Covid-19 African-American patients, who either died in the hospital or survived to discharge between 2 March and 22 May 2020. Patients were divided into two groups, those on ACE-i/ARB at baseline and those not on them. We used Pearson chi-square test for categorical variables, and Student's t test for continuous variables. We performed multiple logistic regression to test the primary and secondary objectives using SAS 9.4. Out of 531 patients included in the analysis, 207 (39%) were on ACE-i/ARB at baseline. Patients in ACE-i/ARB group were older (64 vs. 57 years, P < 0.001), and had higher prevalence of hypertension (96.6 vs. 69.4%, P < 0.001) and diabetes mellitus (55.6 vs. 34.9%, P < 0.001). There was no difference in sex, BMI, other comorbidities, and presenting illness severity among the groups. After adjustment of multiple covariates, there was no difference in outcomes between the two groups including mortality, need for mechanical ventilation, new dialysis, ICU care, as well as composite outcomes. Baseline use of ACE-i/ARB does not worsen outcomes in hospitalized Covid-19 African-American patients.

Oral Probiotic Bifidobacterium Longum Supplementation Improves Metabolic Parameters and Alters the Expression of the Renin-Angiotensin System in Obese Mice Liver.

Obesity and non-alcoholic fatty liver disease (NAFLD) have been increasing at an alarming rate worldwide. Bifidobacterium longum (BL), a common member of the human gut microbiota, has important health benefits through several mechanisms. We evaluated the BL supplementation effects on body metabolism and renin-angiotensin components hepatic expression in mice fed a high-fat diet. Thirty-two male mice were divided into four groups: standard diet + placebo (ST), standard diet + Bifidobacterium longum (ST + BL), high-fat diet + placebo (HFD) and high-fat diet + Bifidobacterium longum (HFD + BL). Following the obesity induction period, the ST + BL and HFD + BL groups were supplemented with Bifidobacterium longum for 4 weeks. Then, body, biochemical, histological and molecular parameters were evaluated. HFD + BL mice had a significant decrease in adipose tissue mass and blood glucose levels, as well as a significant reduction in blood glucose during an intraperitoneal glucose tolerance test. The treatment also resulted in reduced levels of total cholesterol and hepatic fat accumulation. Moreover, we observed an increase in angiotensin converting enzyme 2 (ACE2) and Mas receptor (MASR) expression levels in BL-treated obese mice. These data demonstrate that BL may have the potential to prevent obesity and NAFLD by modulating the mRNA expression of renin-angiotensin system components.

Brain angiotensin II and angiotensin IV receptors as potential Alzheimer's disease therapeutic targets.

Alzheimer's disease (AD) is a neurodegenerative disorder that is multifactorial in nature. Yet, despite being the most common form of dementia in the elderly, AD's primary cause remains unknown. As such, there is currently little to offer AD patients as the vast majority of recently tested therapies have either failed in well-controlled clinical trials or inadequately treat AD. Recently, emerging preclinical and clinical evidence has associated the brain renin angiotensin system (RAS) to AD pathology. Accordingly, various components of the brain RAS were shown to be altered in AD patients and mouse models, including the angiotensin II type 1 (AT1R), angiotensin IV receptor (AT4R), and Mas receptors. Collectively, the changes observed within the RAS have been proposed to contribute to many of the neuropathological hallmarks of AD, including the neuronal, cognitive, and vascular dysfunctions. Accumulating evidence has additionally identified antihypertensive medications targeting the RAS, particularly angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), to delay AD onset and progression. In this review, we will discuss the emergence of the RAS's involvement in AD and highlight putative mechanisms of action underlying ARB's beneficial effects that may explain their ability to modify the risk of developing AD or AD progression. The RAS may provide novel molecular targets for recovering memory pathways, cerebrovascular function, and other pathological landmarks of AD.

Disequilibrium between the classic renin-angiotensin system and its opposing arm in SARS-CoV-2-related lung injury.

A dysregulation of the renin-angiotensin system (RAS) has been involved in the genesis of lung injury and acute respiratory distress syndrome from different causes, including several viral infections. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of pneumocytes, the hallmark of the pandemic coronavirus disease 2019 (COVID-19) involving both alveolar interstitium and capillaries, is linked to angiotensin-converting enzyme 2 (ACE2) binding and its functional downregulation. ACE2 is a key enzyme for the balance between the two main arms of the RAS: the ACE/angiotensin (Ang) II/Ang II type 1 receptor axis (“classic RAS”) and the ACE2/Ang(1–7)/Mas receptor (MasR) axis (“anti-RAS”). The ACE2 downregulation, as a result of SARS-coronaviruses binding, enhances the classic RAS, leading to lung damage and inflammation with leaky pulmonary blood vessels and fibrosis, when the attenuation mediated by the anti-RAS arm is reduced. ACE inhibitors (ACE-I) and Ang II type 1 receptor blockers (ARB), effective in cardiovascular diseases, were found to prevent and counteract acute lung injury in several experimental models by restoring the balance between these two opposing arms. The evidence of RAS arm disequilibrium in COVID-19 and the hypothesis of a beneficial role of RAS modulation supported by preclinical and clinical studies are the focus of the present review. Preclinical and clinical studies on drugs balancing RAS arms might be the right way to counter COVID-19.

Coronavirus Disease 2019 and Hypertension: The Role of Angiotensin-Converting Enzyme 2 and the Renin-Angiotensin System.

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.

Involvement of ACE2/Ang-(1-7)/MAS1 Axis in the Regulation of Ovarian Function in Mammals.

In addition to the classic, endocrine renin-angiotensin system, local renin-angiotensin system (RAS) has been documented in many tissues and organs, including the ovaries. The localization and functional activity of the two opposing axes of the system, viz. ACE1/Ang II/AT1 and ACE2/Ang-(1-7)/MAS1, differs between animal species and varied according to the stage of follicle development. It appears that the angiotensin peptides and their receptors participate in reproductive processes such as folliculogenesis, steroidogenesis, oocyte maturation, and ovulation. In addition, changes in the constituent compounds of local RAS may contribute to pathological conditions, such as polycystic ovary syndrome, ovarian hyperstimulation syndrome, and ovarian cancer. This review article examines the expression, localization, metabolism, and activity of individual elements of the ACE2/Ang-(1-7)/MAS1 axis in the ovaries of various animal species. The manuscript also presents the relationship between the secretion of gonadotropins and sex hormones and expression of Ang-(1-7) and MAS1 receptors. It also summarizes current knowledge regarding the positive and negative impact of ACE2/Ang-(1-7)/MAS1 axis on ovarian function.

Activation of Ang-(1-7)/Mas Receptor Is a Possible Strategy to Treat Coronavirus (SARS-CoV-2) Infection.

The renin-angiotensin system is involved in the pathophysiology of inflammatory diseases through an increase in angiotensin converting enzyme (ACE)/angiotensin (Ang) II/AT1 receptor axis activity. It has been shown that ACE activity is increased in acute respiratory distress syndrome and there is a strong correlation between the level of ACE activity and the degree of lung injury. SARS-CoV-2, the new coronavirus that causes COVID-19, similar to other coronaviruses, was recently shown to use ACE2 as a receptor to get into host cells. However, it has been reported that most of the treatments that stimulates the ACE2/Ang-(1-7)/Mas axis induces beneficial effects, such as, antihypertensive, anti-inflammatory, anti-proliferative, anti-thrombotic and anti-fibrotic. Here we discussed the potential of activation of Ang-(1-7)/Mas pathway as strategy to treat COVID-19.

Exploring the Evidence Implicating the Renin-Angiotensin System (RAS) in the Physiopathology of Mood Disorders.

Mood disorders include Major Depressive Disorder (MDD), Bipolar Disorder (BD) and variations of both. Mood disorders has a public health significance with high comorbidity, suicidal mortality and economic burden on the health system. Research related to mood disorders has evolved over the years to relate it with systemic conditions. The Renin Angiotensin System (RAS) has been noticed to play major physiological roles beyond renal and cardiovascular systems. Recent studies have linked RAS not only with neuro-immunological processes, but also with psychiatric conditions like mood and anxiety disorders. In this comprehensive review, we integrated basic and clinical studies showing the associations between RAS and mood disorders. Animal studies on mood disorders models - either depression or mania - were focused on the reversal of behavioral and/or cognitive symptoms through the inhibition of RAS components like the Angiotensin- Converting Enzyme (ACE), Angiotensin II Type 1 receptor (AT1) or Mas receptors. ACE polymorphisms, namely insertion-deletion (I/D), were linked to mood disorders and suicidal behavior. Hypertension was associated with neurocognitive deficits in mood disorders, which reversed with RAS inhibition. Low levels of RAS components (renin activity or aldosterone) and mood symptoms improvement with ACE inhibitors or AT1 blockers were also observed in mood disorders. Overall, this review reiterates the strong and under-researched connection between RAS and mood disorders.

The Renin Angiotensin System and Bipolar Disorder: A Systematic Review.

Bipolar Disorder (BD) is a chronic a multifactorial psychiatric illness that affects mood, cognition, and functioning. BD is associated with several psychiatric conditions as well clinical comorbidities, particularly cardiovascular diseases. The neurobiology of BD is complex and multifactorial and several systems have been implicated. Considering that the Renin Angiotensin System (RAS) plays an important role in cardiovascular diseases and that recently evidence has suggested its role in psychiatric disorders, the aim of the present study is to summarize and to discuss recent findings related to the modulation of RAS components in BD. A systematic search of the literature using the electronic databases MEDLINE and LILACS was conducted through March 2019. The search terms were: "Bipolar Disorder"; "Renin Angiotensin System"; "Angiotensin 2"; "Angiotensin receptors"; "Angiotensin 1-7"; "ACE"; "ACE2"; "Mas Receptor". We included original studies assessing RAS in BD patients. Two hundred twenty-two citations were initially retrieved. Eleven studies were included in our systematic review. In the majority of studies (6 of 8), the ACE insertion/deletion (I/D) polymorphism did not differ between BD patients and controls. BD patients presented higher plasma renin activity in comparison with controls. The studies evaluating the RAS molecules in BD are very scarce and heterogeneous. The literature suggests a potential role of RAS in BD. Further studies are necessary to investigate this relationship.

Covid-19: the renin-angiotensin system imbalance hypothesis.

The emergency of SARS-CoV-2 in China started a novel challenge to the scientific community. As the virus turns pandemic, scientists try to map the cellular mechanisms and pathways of SARS-CoV-2 related to the pathogenesis of Coronavirus Disease 2019 (Covid-19). After transmembrane angiotensin-converting enzyme 2 (ACE2) has been found to be SARS-CoV-2 receptor, we hypothesized an immune-hematological mechanism for Covid-19 based on renin–angiotensin system (RAS) imbalance to explain clinical, laboratory and imaging findings on disease course. We believe that exaggerated activation of ACE/Angiotensin II (Ang II)/Angiotensin Type 1 (AT1) receptor RAS axis in line with reduction of ACE2/Angiotensin-(1-7)/Mas receptor may exert a pivotal role in the pathogenesis of Covid-19. In this perspective, we discuss potential mechanisms and evidence on this hypothesis.

The Lung Macrophage in SARS-CoV-2 Infection: A Friend or a Foe?

Respiratory, circulatory, and renal failure are among the gravest features of COVID-19 and are associated with a very high mortality rate. A common denominator of all affected organs is the expression of angiotensin-converting enzyme 2 (ACE2), a protease responsible for the conversion of Angiotensin 1-8 (Ang II) to Angiotensin 1-7 (Ang 1-7). Ang 1-7 acts on these tissues and in other target organs via Mas receptor (MasR), where it exerts beneficial effects, including vasodilation and suppression of inflammation and fibrosis, along an attenuation of cardiac and vascular remodeling. Unfortunately, ACE2 also serves as the binding receptor of SARS viral spike glycoprotein, enabling its attachment to host cells, with subsequent viral internalization and replication. Although numerous reports have linked the devastating organ injuries to viral homing and attachment to organ-specific cells widely expressing ACE2, little attention has been given to ACE-2 expressed by the immune system. Herein we outline potential adverse effects of SARS-CoV2 on macrophages and dendritic cells, key cells of the immune system expressing ACE2. Specifically, we propose a new hypothesis that, while macrophages play an important role in antiviral defense mechanisms, in the case of SARS-CoV, they may also serve as a Trojan horse, enabling viral anchoring specifically within the pulmonary parenchyma. It is tempting to assume that diverse expression of ACE2 in macrophages among individuals might govern the severity of SARS-CoV-2 infection. Moreover, reallocation of viral-containing macrophages migrating out of the lung to other tissues is theoretically plausible in the context of viral spread with the involvement of other organs.

Protective Effect of Angiotensin 1-7 on Sarcopenia Induced by Chronic Liver Disease in Mice.

Sarcopenia associated with chronic liver disease (CLD) is one of the more common extrahepatic features in patients with these pathologies. Among the cellular alterations observed in the muscle tissue under CLD is the decline in the muscle strength and function, as well as the increased fatigue. Morphological changes, such as a decrease in the fiber diameter and transition in the fiber type, are also reported. At the molecular level, sarcopenia for CLD is characterized by: (i) a decrease in the sarcomeric protein, such as myosin heavy chain (MHC); (ii) an increase in the ubiquitin–proteasome system markers, such as atrogin-1/MAFbx1 and MuRF-1/TRIM63; (iii) an increase in autophagy markers, such as LC3II/LC3I ratio. Among the regulators of muscle mass is the renin-angiotensin system (RAS). The non-classical axis of RAS includes the Angiotensin 1–7 [Ang-(1-7)] peptide and its receptor Mas, which in skeletal muscle has anti-atrophic effect in models of muscle wasting induced by immobilization, lipopolysaccharide, myostatin or angiotensin II. In this paper, we evaluated the effect of Ang-(1-7) on the sarcopenia by CLD in a murine model induced by the 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) hepatotoxin administered through diet. Our results show that Ang-(1-7) administration prevented the decline of the function and strength of muscle and increased the fatigue detected in the DDC-fed mice. Besides, we observed that the decreased fiber diameter and MHC levels, as well as the transition of fiber types, were all abolished by Ang-(1-7) in mice fed with DDC. Finally, Ang-(1-7) can decrease the atrogin-1 and MuRF-1 expression as well as the autophagy marker in mice treated with DDC. Together, our data support the protective role of Ang-(1-7) on the sarcopenia by CLD in mice.

Food protein-derived antihypertensive peptides in the COVID-19 pandemic: friends of foes?

Food protein-derived antihypertensive peptides in the COVID-19 pandemic: friends of foes?

Could COVID-19 have an impact on male fertility?

The pandemic caused by Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has led to several hypotheses of functional alteration of different organs. The direct influence of this virus on the male urogenital organs is still to be evaluated. However some hypotheses can already be made, especially in the andrological field, for the biological similarity of the SARS‐CoV and SARS‐CoV2. As well as SARS‐CoV, SARS CoV‐2 uses the ‘Angiotensin Converting Enzyme‐2’ (ACE2) as a receptor to enter human cells. It was found that ACE2, Angiotensin (1‐7) and its MAS receptors are present, over in the lung, also in the testicles, in particular in Leydig and Sertoli cells. A first hypothesis is that the virus could enter the testicle and lead to alterations in testicular functionality. A second hypothesis is that the binding of the virus to the ACE2 receptor, could cause an excess of ACE2 and give rise to a typical inflammatory response. The inflammatory cells could interfere with the function of Leydig and Sertoli cells. Both hypotheses should be evaluated and confirmed, in order to possibly monitor fertility in patients COVID‐19+.

Açaí seed extract prevents the renin-angiotensin system activation, oxidative stress and inflammation in white adipose tissue of high-fat diet–fed mice

The role of the renin-angiotensin system (RAS), oxidative stress, and inflammation on the development of obesity and its comorbidities has been extensively addressed. Euterpe oleracea Mart. (açaí) seed extract (ASE), with antioxidant and anti-inflammatory properties and capable to modulate plasma renin levels, has been evidenced as a potential regulator of body mass. We hypothesized that the supplementation with ASE might exert beneficial effects on obesity-related white adipose tissue changes and metabolic disorders by interfering with the local adipose tissue overexpression of RAS, inflammation, and oxidative stress in C57BL/6 mice fed a high-fat (HF) diet. The animals were fed a standard diet (10% fat, control), 60% fat (HF), HF + ASE (300 mg/kg per day) and HF + ENA (enalapril, 30 mg/kg per day) for 12 weeks. ASE and ENA prevented weight gain and adiposity, adipocyte hypertrophy, dyslipidemia, and insulin resistance. In adipose tissue, ASE increased the insulin receptor expression and reduced renin and AT1 receptor expression, which was associated with decreased plasma levels of renin and angiotensin II. Differently, ENA increased the expression of angiotensin-conversing enzyme 2, AT2, B2, and Mas receptors in adipose tissue. Also, ASE but not ENA decreased malondialdehyde and 8-isoprostane levels in adipose tissue. Finally, ASE and ENA reduced the adipose tissue inflammatory markers tumor necrosis factor alpha and interleukin 6. These results demonstrate that ASE prevented the adipocyte hypertrophy, obesity, hyperlipidemia, hyperglycemia, and insulin resistance in HF diet–fed mice. The downregulation of RAS in adipose tissue, reducing oxidative stress and inflammation, may contribute to the prevention of obesity-related disorders.

The Renin-Angiotensin-Aldosterone System in Coronavirus-19 Disease Pathogenesis: Extracting the Devil in the Details.

Coronavirus 2019 disease (COVID-19) was first recognised as an acute febrile respiratory syndrome. Soon, it was realised that acute kidney injury, myocarditis, cytokine activation and prothrombotic disseminated intravascular coagulation are also part of the syndrome complex. Currently, it is being recognised as causing microangiopathy as well as thrombo-embolic complications. The SARS-CoV-2 coronavirus enters cells via the ACE2 (Angiotensin converting enzyme-2) receptor and leads to its downregulation. The loss of ACE2 is postulated to cause activation of the Renin Angiotensin Aldosterone System (RAAS) that contributes to cardiac and renal pathology. Supporting the hypothesis that ACE2 loss can explain the entire pathology, we have reviewed the available literature to determine mechanistic associations between RAAS and the various manifestations of COVID-19. ACE2 dependent protective pathways include the Angiotensin(1-7)/Mas receptor and Alamandine/MrgD receptor pathways. These are anti-hypertensive, anti-inflammatory, and anti-thrombotic. Loss of ACE2 leads to Angiotensin II and aldosterone accumulation that causes thrombosis via release of Plasminogen Activator Inhibitor-1(PAI-1). Altered ACE1/ACE2 balance can activate immune cells and cause polarization of macrophages into M2-inflammatory phenotype. Animal models of various viral pneumonias have previously shown that ACE2 loss is associated with severe lung injury. Angiotensin II and aldosterone are known causes of cardiomyopathy and also potentiate acute kidney injury. There is some emerging evidence that inhibitors of canonical RAAS such as ACE inhibitors, Angiotensin receptor blockers, and statins may have mortality benefit in COVID-19. Heparin inhibits both thrombosis and RAAS, and has definite mortality benefit at least in a subset of COVID-19 patients. Activated Protein C may be helpful for the microangiopathic thrombosis. We strongly advocate that treatment strategies for COVID-19 should include synergistic targeting of the RAAS and coagulation systems.