key: cord-337082-2xas41mj
authors: Akoumianakis, Ioannis; Filippatos, Theodosios
title: The renin–angiotensin–aldosterone system as a link between obesity and coronavirus disease 2019 severity
date: 2020-06-22
journal: Obes Rev
DOI: 10.1111/obr.13077
sha: 
doc_id: 337082
cord_uid: 2xas41mj

Coronavirus disease 2019 (COVID‐19), caused by the severe acute respiratory distress coronavirus 2 (SARS‐CoV2), is a rapidly evolving pandemic challenging the world and posing unprecedented public health issues. Current data show that COVID‐19 is associated with increased disease severity in individuals with obesity. Obesity is usually associated with dysregulated renin–angiotensin–aldosterone (RAAS) axis. RAAS has also been implicated in acute lung injury as well as myocardial injury and has thus attracted interest as a potential regulator of COVID‐19 severity. Whilst research all over the world is still struggling to provide a detailed characterization of the biology of SARS‐CoV2 and its associated disease profile, it has become evident that SARS‐CoV2 uses the membrane‐bound form of angiotensin‐converting enzyme 2 (ACE2) as a receptor for cell internalization. ACE2 is a protective component of the RAAS axis and is downregulated after SARS‐CoV2 infection. The RAAS axis could thus be a link between obesity and COVID‐19 severity; therefore, more accurate understanding of the underlying mechanisms would be needed with the hope of proposing efficient therapeutic interventions.

The Coronavirus disease 2019 (COVID-19) is a rapidly evolving pandemic. 1 Despite intensive research on the field, self-isolation measures and supportive treatment remain the mainstay of prevention and treatment, respectively. 2 Interestingly, the aetiologic agent behind COVID-19, severe acute respiratory distress coronavirus 2 (SARS-CoV2), interacts with angiotensin-converting enzyme 2 (ACE2), a part of the renin-angiotensin-aldosterone (RAAS) axis, suggesting therapeutic implications for this axis. [3] [4] [5] Obesity, usually defined by body mass index (BMI) > 30 kg/m 2 , is characterized by visceral adipose tissue (AT) expansion and inflammation. 6 As such, the waist-to-hip ratio has been proposed as a more accurate marker of visceral obesity, although less used in clinical practice. 7 Inflamed AT secretes pro-inflammatory cytokines, adipokines and other molecules with broad pathophysiological effects. [7] [8] [9] [10] [11] [12] Indeed, visceral obesity is associated with conditions such as hypertension, diabetes and dyslipidaemia. 9, 13 Evidence suggests that RAAS signalling is upregulated in obesity, potentially being a target in obesity-associated diseases. [14] [15] [16] Observational findings indicate that COVID-19 severity is associated with the presence of co-morbidities such as hypertension, diabetes and obesity. [17] [18] [19] [20] However, the possible independent association of obesity with COVID-19 clinical features has not been examined in large appropriately designed patient cohorts. 17 Optimal interventions in COVID-19 patients with obesity are controversial because of lack of underlying mechanism characterization. We hereby discuss the potential role of RAAS in COVID-19 patients with obesity, focusing on lung and myocardial injury, the main causes of adverse outcome in COVID-19.

RAAS regulates fluid balance, blood pressure and cardiorenal function. 21 RAAS activation is initiated upon secretion of renin, an enzyme produced in the pericytes of the glomerular afferent arterioles and the juxtaglomerular apparatus of the nephron. 21 Secretion stimuli include reduced glomerular blood flow, reduced tubular sodium flow and sympathetic stimulation. 21, 22 Renin converts angiotensinogen to angiotensin I (AngI), which is transformed to angiotensin II (AngII) via angiotensin-converting enzyme 1 (ACE1), 21,23 causing vasoconstriction, adrenal aldosterone secretion and renal retention of sodium and water. 14, 16 Several pathogenic mechanisms are able to bypass the physiological RAAS loop. [24] [25] [26] Reduced effective circulating blood volume (as in congestive heart failure) is sensed as virtual hypovolaemia by the kidneys, which, coupled with sympathetic activation, leads to inappropriate RAAS activation. 27 Pro-inflammatory conditions such as atherosclerosis and obesity-related AT inflammation may also increase AngII and aldosterone secretion by macrophages and adipocytes. [28] [29] [30] [31] RAAS overactivation, in turn, regulates macrophage M1 activation, oxidative stress, fibrosis and pro-inflammatory cytokine production. 32, 33 ACE2 regulates RAAS by degrading AngII to Ang (1-7) as well as by alternatively cleaving AngI to Ang (1-9) instead of AngII, 34 inhibiting downstream AngII signalling. 33 Interestingly, Ang (1-7) has its own receptor, Mas, which can reduce pro-inflammatory cytokine release, facilitate vasorelaxation and ameliorate tissue fibrosis in experimental models of atherosclerosis, obesity, asthma and heart failure. [35] [36] [37] RAAS is pharmacologically modifiable by angiotensin type 1 (AT1) receptor blockers (ARBs) and ACE1 inhibitors, which are widely used in clinical practice. 33 By blocking downstream AngII signalling, ARBs and ACE1 inhibitors may have a stimulatory feedback effect on ACE2, although in vivo studies on this are inconsistent. 33, 38, 39 Currently, pharmacological RAAS inhibition is assumed to increase ACE2, particularly after long-term treatment, although the clinical relevance of this is controversial. 33 

Although inter-individual differences may be observed, obesity usually induces RAAS activation via complex mechanisms. 15 Obesity results in dysregulated AT, which secretes angiotensinogen, mineralocorticoids and mineralocorticoid releasing factors such as leptin, enhancing the angiotensin/aldosterone axis and further stimulating the adrenal glands towards aldosterone production. 14, 15, 30 Furthermore, obesity is associated with endothelial dysfunction and hyperinsulinaemia, which may further exaggerate endothelial dysfunction. 40 These result in disturbed renal blood flow and elicit a renal response similar to that of hypovolemia, leading to enhanced RAAS activation. 15, 30 AT may also secrete cathepsins, which promote enzymatic conversion of AngI to AngII. 30 Obesity also interacts with RAAS via neurohormonal mechanisms.

Firstly, obesity is associated with sympathetic nervous system activation, a potent stimulator of renin secretion. 41 Leptin is an adipokine that is upregulated in obesity and acts in various regions of the central nervous system such as the hypothalamus and the brainstem, inducing sympathetic activation as well as food intake, further stimulating renal renin secretion. 15, 42 Interestingly, AngII increases adrenal catecholamine secretion and target organ sympathetic specificity via AT1 receptors, 26, 43 whilst it may modulate food intake via hypothalamic effects, 44 suggesting a bidirectional neurohormonal crosstalk with obesity that warrants further investigation in humans.

Obesity is also associated with reduced expression of ACE2 in AT, which has been linked with a variety of obesity-associated complications such as exaggeration of heart failure, hypertension and renal failure. 36, 45, 46 ACE2 may exert direct anti-obesity effects by promoting AT browning and lesser white AT accumulation 46 and ameliorating AT inflammation 36, 47 as evidenced in mechanistic studies, warranting further investigation in humans.

The RAAS axis is implicated in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) via AngII signalling. In in vitro studies, AngII induces collagen production in lung fibroblasts via transforming growth factor beta (TGFβ) and induces pneumonocyte apoptosis. 48 In an in vivo mouse model of ALI, AngII induced lung fibrosis, which was reversed by losartan, an ARB. 49 In a rat model of lipopolysaccharideinduced sepsis, losartan upregulated lung ACE2 and reduced histopathological lung damage and production of pro-inflammatory cytokines such as interleukin 6 (IL6) and tumour necrosis factor alpha (TNFα). 50 Similarly, losartan reduced nuclear factor kappa beta (NFκB) signalling in lung tissue and plasma IL6, TNFα and interleukin 1 beta (IL1β), improving ALI/ARDS in mice. 51 Losartan may reduce alveolar cell permeability, attenuating pulmonary oedema in mouse models of ALI/ARDS. 52 Importantly, ACE2 may have protective effects in the context of ALI and ARDS, as evidenced by in vivo mouse models. 53 In mice, ACE2 deletion worsened ALI via increased alveolar cell permeability and pulmonary oedema, 54 whilst ACE2 demonstrated antiinflammatory effects in sepsis-related ALI. 55 ACE2 may regulate alveolar cell permeability by antagonizing the effects of vascular endothelial growth factor alpha (VEGFα). 56 In human studies, genetic polymorphisms of the ACE1 gene have been linked with adverse outcome following ARDS. 57, 58 AngII plasma levels have been linked with ALI severity following other viral infections such as H7N9 influenza infection 59 ; however, the biomarker potential of AngII is compromised by its large between-patients variability. 60 

RAAS affects cardiac function owing to multiple mechanisms as described by various experimental mechanistic studies. AngII and aldosterone induce myocardial remodelling and fibrosis, adversely influencing the pumping ability of the heart. 61 AngII also contributes to arrhythmogenic re-entry substrate formation via myocardial fibrotic mechanisms, which increase arrhythmia risk. 62 53 Similarly, SARS-CoV2 appears to also downregulate ACE2 upon cell entry in vitro. 76 It is unclear whether ACE2 contributes to COVID-19 pathophysiology via its downregulation, beyond its SARS-CoV2 receptor properties. ACE2 is expressed in both alveolar cells and cardiomyocytes, which may explain the severe lung and myocardial injury observed in COVID-19 patients. 53, 77 Given the role of ACE2 in regulating both COVID-19 infection and RAAS activation, it has been speculated that RAAS may be of importance in SARS-CoV2 severity. In a small cohort of COVID-19 patients, plasma AngII levels were positively correlated with SARS severity and viral load. 78 Recombinant ACE2 reduces AngII levels and improves ALI in experimental models of influenza A H5N1 and respiratory syncytial virus infections, 79, 80 whilst it may reduce ARDS severity in humans. 81 Based on these observations, recombinant ACE2 may be a modifiable RAAS regulatory factor with beneficial effects in COVID-19.

Obesity is a significant risk factor for mechanical ventilation and adverse outcome in a number of viral pneumonias. 17 The Centers for Disease Control and Prevention consider patients with morbid obesity (BMI > 40 kg/m 2 ) as being at high risk for influenza complications. 82 During the 2009 H1N1 pandemic, more than 50% of patients requiring hospitalization suffered from obesity (BMI > 30 kg/m 2 ), which was recognized as an independent risk factor for adverse outcome. 17, 82 Consistently, current clinical experience indicates that obesity is associated with increased COVID-19 severity and adverse outcomes. 17 85 Further retrospective studies have shown that obesity is an independent risk factor for mechanical ventilation need in COVID-19, as well as a prominent risk factor in patients under 60 years of age. 86, 87 On the other hand, obesity is also associated with a number of comorbidities including hypertension and diabetes, 83 With definitive mechanistic studies still pending, the most relevant question is whether the interaction between obesity, RAAS and COVID-19 is modifiable. Efficient targeting of obesity is achievable via lifestyle changes, pharmacological agents such as glucagon-like peptide 1 agonists and bariatric surgery in humans. [92] [93] [94] Weight loss by as little as 5% may result in meaningful RAAS inhibition in humans. 95 Interestingly, dietary sodium restriction as well as exercise may be effective in RAAS blockade in humans. 95, 96 Obesity-targeting lifestyle, dietary and pharmacological interventions may thus cause rapid changes in RAAS activation in patients at risk for COVID-19.

As mentioned earlier, RAAS is subject to direct modification by ACE1 inhibitors and ARBs, which have been extensively used in clinical practice against diseases such as hypertension and nephropathy. 33 On the other hand, the use of such agents in COVID-19 is controversial, because of their potential to upregulate ACE2, thus increasing SARS-CoV2 infection susceptibility. 5, 33 However, this is hypothetical, with recent meta-analyses showing no increased risk of ACE1 inhibitors or ARBs with regard to COVID-19 severity. 97 Considering the detrimental effects of AngII on lung and myocardial biology, it has been hypothesized that ACE1 inhibitors and ARBs may actually protect against severe COVID-19 disease. 33 A retrospective study in hypertensive patients with COVID-19 showed that in-hospital use of ACE1 inhibitors and ARBs was, in fact, associated with reduced mortality. 98 Inhibition of the strong detrimental effects of AngII by ACE1 inhibitors and ARBs may be more important than the questionable effect of these drugs on ACE2 levels. The latter seems unlikely to drastically affect COVID-19 severity given the exponential multiplication of the virions and the small dependency on absolute ACE2 levels.

The renin-angiotensin-aldosterone (RAAS) axis as a link between obesity and coronavirus disease 2019 (COVID-19) severity. Obesity is associated with adipose tissue (AT) inflammation, which leads to the secretion of angiotensinogen, mineralocorticoid enhancers and cathepsins. Obesity also induces renal RAAS activation via neurohormonal signals mediated by leptin, sympathetic activation and renal vasomotor effects of hyperinsulinaemia and endothelial dysfunction. SARS-CoV2 infects host cells such as alveolar cells via angiotensin-converting enzyme 2 (ACE2) and causes downstream ACE2 and angiotensin (1-7) (Ang [1] [2] [3] [4] [5] [6] [7] ) downregulation. The above synergistically result in increased levels of angiotensin II (AngII) in the lung, leading to increased alveolar cell permeability and apoptosis, fibrosis and inflammation. These pathogenic mechanisms enhance the severity of pulmonary oedema, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Enhanced AngII signalling in the myocardium also causes heart overload, myocardial inflammation and cardiac remodelling, which contribute to adverse outcome in COVID-19. Recombinant ACE2 (rec. ACE2) may scavenge SARS-CoV2 virions and also inhibit AT inflammation, AngII formation and downstream events. ACE1 inhibitors reduce AngII formation, whilst angiotensin receptor blockers (ARBs) reduce the downstream effects of AngII. Thus, in theory, these drug classes may decrease the adverse effects of COVID-19 in lungs and the myocardium AngII signalling may also be modified by indirect ways besides ACE1 inhibition and ARB blockade. In the presence of AT1 blockade by ARBs, AngII may cross-activate angiotensin type II (ATII) receptors, which could convey protective effects in the context of ALI, although this is only hypothetical at this point. 99 Furthermore, it has been proposed that recombinant ACE2 infusion could improve outcome in COVID-19 via a two-fold mechanism involving neutralization of virions prior to membrane ACE2 binding and cell entry as well as enzymatic reduction of AngII, shifting the balance from AngII towards Ang (1-7) . 53, 99 To this end, preliminary clinical trials are being conducted to explore the role of recombinant soluble ACE2 in COVID-19 (NCT04287686) and the role of losartan in COVID-19 in patients having not received ACE1 inhibitor or ARB treatment previously (NCT04312009, NCT04311177). 33 

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How to cite this article: Akoumianakis I, Filippatos T. The renin-angiotensin-aldosterone system as a link between obesity and coronavirus disease 2019 severity