key: cord-0769730-6vjinjln
authors: Babajani, Fatemeh; Kakavand, Atefeh; Mohammadi, Hossien; Sharifi, Armin; Zakeri, Saba; Asadi, Soheila; Afshar, Zeinab Mohseni; Rahimi, Zohreh; Sayad, Babak
title: COVID‐19 and renin angiotensin aldosterone system: Pathogenesis and therapy
date: 2021-11-17
journal: Health Sci Rep
DOI: 10.1002/hsr2.440
sha: 869abf5beceb5baa07096a06e5b9ee627f73266e
doc_id: 769730
cord_uid: 6vjinjln

AIMS: The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) binds to the ACE2 component of the renin‐angiotensin aldosterone system (RAAS) and infects the human cells. The aims of the present review were to look at the role and alteration of the RAAS components in SARS‐CoV‐2 infection, therapeutic approaches, and clinical trials in this field. METHODS: We surveyed the literature (PubMed, Web of Science, and Scopus) till August 18, 2021, and 59 published papers regarding the components of the RAAS and their role and alterations in SARS‐CoV‐2 infection along with various COVID‐19 therapies based on the RASS components were included in the study. RESULTS: ACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor inhibitors are agents that significantly enhance the ACE2 and Ang‐(1‐7) levels, which can be suggestive for their role as therapeutics against SARS‐CoV‐2 infection. Beta‐adrenergic blockers, which negatively regulate renin release from juxtaglomerular cells, and vitamin D, as a regulator of the RAAS and renin expression, are proposed therapeutics in the treatment of COVID‐19. Some antihyperglycemic agents could be potentially protective against COVID‐19‐induced lung injury. Also, the inhibition of the Janus kinase/signal transducer and activator of the transcription pathway as a potential treatment for COVID‐19 has been suggested. Finally, resveratrol, an antioxidant that can suppress Ang II, has been suggested as an adjunct to other therapies. CONCLUSION: Regarding the suggested potential therapies for COVID‐19, there are many clinical trials whose results might change the treatment strategies of SARS‐CoV‐2 infection. So, the results of well‐organized clinical trials on the efficacy and safety of the mentioned agents in the treatment of COVID‐19 will be useful in the management and therapy of the disease.

The SARS-CoV-2, similar to SARS-CoV, uses the ACE2 for entering the cells. 11 The binding of SARS-CoV-2 to the membrane-bound ACE2 as its functional receptor facilitates the entry of the virus into the cells. 4 Four main structural proteins, spike (S), envelope (E), nucleocapsid (N), and membrane (M), have been detected in SARS-CoV-2.

The S proteins, which are large membrane-linked glycoproteins, have a critical role in viral infection through binding to their receptor, ACE2, on host cells and also by membrane fusion. The affinity between S1 subunit, one of the two subunits of S protein, and host ACE2 receptor determines host susceptibility to SARS-CoV2 infection. 12 The SARS-CoV-2 is attached to the cell surface through binding to ACE2 in a multistep variation of conformational state, and the membrane fusion step is started. After S1 receptor-binding domain binds to ACE2, transmembrane protease/serine subfamily 2 (TMPRSS2) degrades the S2 domain to facilitate membrane fusion.

It seems that SARS-CoV-2 cell entry leads to downregulation of membrane-bound ACE2, which results in the lung injury and vasoconstriction. Moreover, other membrane proteins are necessary for SARS-CoV-2 entry into the cells by priming and activation of the S protein. 4 Therefore, ACE2, which is found in the human lower respiratory tract, acts as a cell receptor for SARS-CoV. The ACE2 is also expressed in the mucosa of the oral cavity, with higher expression in tongue than other oral regions. 11 Hence, the ACE2-expressing cells in oral tissues could be the possible routes of COVID-19 entry. 11 In addition, ACE2 is highly expressed in type II epithelial cells where its tissue activity is higher than plasma. 13 Furthermore, the activity of the RAAS and ACE2 is high in the lungs. 13 Moreover, other organs with high ACE2-expressing cells are at high risk for COVID-19 infection.

The high affinity of SARS-CoV-2 to ACE2 could explain the greater infectivity of this virus compared to other human CoVs. 4 Age, diabetes mellitus, hypertension, chronic respiratory diseases, chronic kidney diseases, cardiovascular diseases, and cancers are risk factors for COVID-19 and its severity. The most affected population with COVID-19 is individuals with age group of 50 to 60 years. A positive association between severity and aging has been observed, which seems to be due to the higher prevalence of preexisting comorbidities, and lifespan physiological oscillation of the RAAS components. In the process of aging, the RAAS axes equilibrium is modified, and upregulation of ACE/Ang II/AT1R and increased plasma renin activity occurs. The presence of comorbidities such as hypertension and diabetes was associated with unfavorable outcomes in patients with COVID- 19 . These comorbidities are closely correlated with highly increased activation of ACE/Ang II/AT1R axis. Therefore, severe forms of COVID-19 can result from the previous history of the RAAS imbalance, which favors the inflammatory state. However, the ACE2 expression might be crucial in the prognosis of the disease due to utilizing RAAS inhibitors by several diabetic and/or hypertensive patients for management of the classical axis upregulation. 4 The prognosis of COVID-19 is also dependent on the sex, as the ACE2 expression in females is higher than males. 13 Regarding age-and sex-dependent expression of ACE2, there are many aspects that need to be elucidated.

At present, there is no approved antiviral drug for the treatment of COVID-19. However, in addition to approaches working on antiviral therapy, others have focused on the components of the RAAS. In the present review, we have looked at the role and alteration of the RAAS components including ACE2 and Ang- (1) (2) (3) (4) (5) (6) (7) in SARS-CoV-2 infection, therapeutic approaches, and clinical trials in this field. Also, we described therapies and clinical trials using ACEIs, angiotensin receptor blockers (ARBs), and renin inhibitors in SARS-CoV-2 infection and COVID-19 outcomes. Furthermore, the therapies and clinical trials designed based on the crosstalk of the RAAS with kallikrein/kinin pathway, hyaluronic acid (HA) degradation, neprilysin (NEP) activity, glucose homeostasis, and Janus-activated kinase (JAK) pathway and the role of antioxidant of resveratrol in relation to the Ang II are discussed.

In this review, we surveyed the literature (PubMed, Web of Science, and Scopus) till August 18, 2021, and 59 published papers discussed the RAAS pathway and its cross talk with the kallikrein/kinin pathway, HA degradation, and NEP activity, and their role and alterations in SARS-CoV-2 infection were included in the present review. Also, papers and clinical trials, according to "ClinicalTrials.gov" website related to various COVID-19 therapies based on recombinant human ACE2 (rhACE2), Ang- 

In a study on the treatment of seven patients with COVID-19 pneumonia in China, the role of ACE2 in SARS-CoV-2 infection was confirmed using intravenous transplantation of mesenchymal stem cells (MSCs) that were negative for both ACE2 and the type II transmembrane serine proteases TMPRSS and free from COVID-19 infection.

The pulmonary function and the symptoms of patients were significantly improved 2 days after MSCs transplantation. 14 Some studies suggested that metallopeptidase domain 17 (ADAM17) is essential for cellular entry of SARS-CoV through binding SARS-S to ACE2 that triggers processing of ACE2 by ADAM17 and facilitates ACE2 shedding into the extracellular space, and increases SARS-CoV uptake into cells. 15, 16 However, Heurich et al using in vitro studies indicated that proteolysis ACE2 by TMPRSS2 and HAT augmented the SARS-Sdriven entry to the cells with highly increased viral uptake. Also, their study demonstrated a competition between TMPRSS2 and ADAM17 for ACE2 cleavage, although only processing of ACE2 by TMPRSS2 enhanced entry of the virus to the cells. 17 There are evidences of the significant hypomethylation of the promoter region of the ACE2 gene on the X chromosome and its overexpression in peripheral blood mononuclear cells of patients with lupus erythematous. 18 The rhACE2 or adenoviral (Ad)-ACE2 has been used as a therapeutic agent in animal diseases models and also has been used and well-tolerated in a clinical trial including 44 patients with acute respiratory distress syndrome (ARDS). 19 Animal studies indicated that the rhACE2 acts as an important negative regulator of Ang II and inhibits adverse myocardial remodeling. 20 The ACE2 activity in the circulation is significantly increased by rhACE2, which is accompanied by effective decline of Ang II levels and increased production of Ang-(1-7)

from Ang II. Injection of a chimeric fusion of rACE2-Fc (immunoglobulin fragment Fc segment) increased the overall Ang II-conversion activities in blood up to 100 times and recovered induced hypertension in mice. Also, rACE2-Fc decreased kidney and cardiac fibrosis. 21 Verma et al suggested a combination therapy by applying GapmeR technology with rhACE2 in the treatment of COVID-19 patients.

GapmeR is an antisense single-stranded DNA molecule that is designated to a specific target and binds to the SARS-CoV-2 RNA, and then, the produced DNA-RNA hybrid is degraded by intracellular RNAase-H.

On the other hand, rhACE2 blocks entering the virus to the host cells. 22 Moreover, the protective role of soluble ACE (sACE) is justified by the absence of increased risk of SARS-CoV-2 infection in inflammatory bowel disease (IBD) patients because of sACE2 upregulation in the peripheral blood of these patients. 23 In another approach, cyclodextrin (CD)-sACE2 inclusion has been suggested for the treatment of this infection. 24 Various compounds of aerosolized sACE2 to be directly inhaled into the lungs, intravenous infusion of sACE2, and ophthalmic and nasal drops made from CD-sACE2 inclusion compounds have been suggested for the treatment of COVID-19. 25 Searching the "ClinicalTrials.gov" website until July 14, 2021 has revealed three clinical trials currently underway, evaluating rhACE2 in COVID-19 patients (Table 1 ).

A modified version of Ang-(1-7) with long-lasting release property, hydroxypropyl-β-cyclodextrin-Ang-(1-7) complex that allows the oral administration of this compound has been suggested as a therapeutic compound in COVID-19. Intravenous infusion of cyclic Ang-(1-7), a more resistant form of Ang-(1-7) to enzymatic hydrolysis, has had long-term vasorelaxant effects in animal studies. 24 

ACE inhibitors such as enalapril and lisinopril elevate tissue/plasma ACE2 levels in animal studies. The angiotensin receptor blockers/ angiotensin receptor antagonists/sartans (losartan, olmesartan, irbesartan, and telmisartan) increase tissue/plasma or urinary ACE2 levels in animal models and also in hypertensive patients (olmesartan).

Furthermore, mineralocorticoid receptor inhibitors (MCRIs)/aldosterone antagonists increase ACE2 activity in patients with heart disease (spironolactone) and in mice (eplerenone). 26 There are some molecular models and studies using human tissues and experimental animal models, which investigate the influence of RAAS inhibitors on ACE2 activity. In a molecular model based on studies conducted in both animals and human tissues to examine the effect of pharmacological therapy on the RAAS pathway, a relationship between the RAAS pathway and SARS-CoV infection was found. Moreover, this model demonstrated that treatment with ARBs, sartans, alone or in combination with ACEIs resulted in increased cell membrane ACE2 activity with a higher risk of viral infection. However, treatment with ACEIs alone have had a protective role due to the decreased ACE2 levels on cell membranes and enhanced ACE2 in the plasma. This model was confirmed in a rapidly recovering patient of SARS-CoV-2 infection who had been on long term and overuse of ACEIs. 12 Although ACE2 activity is not inhibited by traditional ACEIs, the use of ACEIs in animal experiments has indicated an increased ACE2 level and activity. 13 Some animal studies have shown that ACEIs or ARBs increase ACE2 levels. 27 Also, blockade of AT1R by losartan has diminished lung damage in mice who had been administered the SARS-CoV-1 glycoprotein spike. 28 There are some experiences from China regarding RAAS inhibitors and COVID-19. In a retrospective review of medical records from hospitalized COVID-19 patients with hypertension, it was observed that the inflammatory response was attenuated in patients who received ACEIs or ARBs therapy, through the inhibition of IL-6 levels, and also there was a lower rate of severe diseases in these cases. 29 This study suggested the potential benefit of using ACEIs or ARBs in the improvement of clinical outcomes of COVID-19 patients with hypertension. 29 Analysis of COVID-19 cases in China demonstrated that the case fatality rate in patients with comorbidities (cardiovascular diseases, diabetes mellitus, and hypertension) was much higher than those without comorbidities. However, the age as a confounder should be considered in the evaluation of the high fatality rates. 30 A large meta-analysis including 28 872 SARS-CoV-2-infected patients taking ACEIs/ARBs indicated the absence of association between the use of ACEIs/ARBs and the severity and mortality of COVID-19. However, taking ACEIs/ARBs in hypertensive patients had beneficial effects leading to 0.67 times less incidence of fatal/ critical outcomes compared to those not on ACEIs/ARBs (P = .01).

Furthermore, being treated with a ACEIs/ARBs was associated with a significantly lower risk of death. 31 In addition, in a meta-analysis including 25 observational studies, neither ACEIs nor ARBs were associated with incidence of SARS-CoV-2 infection, hospitalization, severe or critical forms of the disease, intensive care unit admission, and SARS-CoV-2-related death. 32 Registries of clinical trials related to the RAAS inhibitors are listed in Table 3 patients. An association between HA with pulmonary thrombosis and/or ground-glass opacities has been observed in radiological findings. 35 It was found that Ang II increases CD44 expression and hyaluronidase activity. 35 3.7 | Neprilysin, the RAAS, and COVID-19

The role of NEP in COVID-19 is controversial. It has been suggested that increased NEP activity might be involved in decreased COVID-19 severity by diminishing Ang II formation and directing Ang I to generate Ang-(1-7). Also, NEP degrades BKs and therefore prevents the activation and recruitment of the inflammatory cells. 37 

Some antihyperglycemic medications have the anti-inflammatory effects (metformin, sulfonylurea, and dipeptidyl peptidase four inhibitors) in animal models with lung injury, so they can potentially be protective against COVID-19-induced lung injury. 39 Seven clinical trials related to antihyperglycemic agents are depicted in Table 5 .

Inhibition of the JAK/signal transducer and activator of the transcription (STAT) signaling pathway has also been suggested as a potential treatment for COVID-19. 40 Baricitinib is an oral JAK1 and JAK2 inhibitor that has also been suggested for COVID-19 treatment. Baricitinib reduces host cell infection through numb-associated kinases inhibition and has anti-cytokine and anti-inflammatory activity. In a case series The clinical trials examining JAK inhibitors are indicated in Table 6 .

Resveratrol, a natural polyphenol, is a potent antioxidant that its antiviral activity against a variety of viruses including Middle East

Respiratory Syndrome Coronavirus (MERS-CoV) infection has demonstrated. 43, 44 Three ongoing clinical trials using resveratrol are demonstrated in Table 7 .

The role of ACE2 in SARS-CoV-2 infection has been confirmed using intravenous MSCs that were both ACE2, and TMPRSS2 negative and free from COVID-19 infection. 14 The ACE2 overexpression in human endothelial cells attenuated the oxidative stress induced by Ang II and subsequent increased monocyte adhesion. 13 Downregulation of ACE2 The imbalance between both RAAS axes could result in pulmonary, inflammatory/immune, and hematological disturbances. 4 The ACE2

interaction with the virus decreases its level in infected individuals with SARS-CoV. Therefore, it is suggested that decreased pulmonary ACE2 activity along with cytokines expression is involved in the pathogenesis of lung inflammation. 12 In addition, epigenetic dysregulation (hypomethylation) of ACE2 has been considered a mechanism for increased risk and severity of SARS-CoV-2 infections. 18 Currently, there is no approved effective medication for COVID-19 treatment.

However, some researches focused on the therapeutic agents affecting the RAAS pathway, due to its critical role in the regulation of body homeostasis. Moreover, it has been known that ACE2 has a protective role in ARDS, which is a potentially life-threatening form of acute lung injury. Therefore, the development of spike protein-based vaccines and therapeutics with increased ACE2 activity has been suggested as approaches for the management of COVID-19. The beneficial effects of ACE2-enhancing agents in SARS-CoV-2-infected patients might be due to increased ACE2 activity that results in activation of the ACE2-Ang-(1-7)-Mas R component of the RAAS pathway, which is an anti-inflammatory, anti-fibrotic, and anti-oxidative stress signaling. 26 The activation of the RAAS pathway through binding of SARS-CoV-2 to ACE2 results in diminished ACE2 levels, which is compatible with systemic manifestations of COVID-19. 45 The rhACE2 could be used as a potential treatment for hypertension, heart failure, kidney damage, and liver fibrosis. 21, 46, 47 The rhACE2 increased the vasculoprotective effects of ACEIs or ARBs. 13 Simultaneous inhalational administration of rhACE2 and SARS-CoV-2-targeted GapmeR has been suggested as a therapy for COVID-19 as rhACE2 completely eliminates the extracellular virus and GapmeR inhibits viral replication. 22 However, rhACE2, with its large molecular size, has limited penetrance and activity against tissue RAAS. 45 Another suggested compound, sACE2, is produced by ADAM17 in the physiological situations and in SARS-CoV infection that cleaves and releases the extracellular domain of ACE2 (sACE2), 15, 47 with even maintained enzymatic activity. 48 The sACE2 can compete with ACE2 for binding to the S protein of SARS-CoV and consequently inhibits cellular infection with SARS-CoV. 25, 49 It has been indicated that SARS-CoV-1 spike protein binding to ACE2 activates disintegrin and ADAM17, known as tumor necrosis factor-α (TNF-α) converting enzyme, and induces ACE2 shedding through a process tightly coupled with the production of TNF-α. 39 There are controversies about the role of ADAM17 and sACE2 in viral infections. TMPRSS2 enhances the SARS-CoV entry through ACE2 cleavage, which might increase viral uptake, and SARS-S cleavage, which in turn activates the S protein of the virus for membrane fusion. 17 Increasing evidence suggests that the infectious mechanisms of SARS-CoV and SARS-CoV-2 are approximately the same; thus, sACE2 can prevent the SARS-CoV-2 infection. 25 Since the sACE2 level is upregulated in the peripheral blood of IBD patients, it could limit the SARS-CoV-2 infection through competition with full-length ACE2 for binding to SARS-CoV-2. 23 Some studies have figured out the mechanism of binding SARS-CoV-2 spike glycoprotein to ACE2 in order to help design medications that inhibit the spike glycoprotein of SARS-CoV-2, which has a critical role in viral infection and fusion with ACE2. 50 The

CDs, macrocyclic molecules with pyranose units linked by the α-1,4-glycoside chain, can enclose highly hydrophobic molecules in their hydrophobic cavities, so as the complex of CD and sACE2 can effectively improve water solubility of sACE2 and be effective in drug atomization inhalation. 25 

Angiotensin-(1-7) is one part of the protective the RAAS axis. This peptide binds to AT2R and Mas R. Therefore, in situations with limited complex, allows the oral administration of this compound and using this compound in the treatment of COVID-19 patients. 24 

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which suppress the ACE/Ang II/AT1R axis, and mineralocorticoid receptor inhibitors are commonly used in the treatment of hypertensive patients. These agents significantly increase the ACE2

and Ang-(1-7) levels, which is suggestive for their protective effect against virus-induced lung injury. 12, 29 Angiotensin-(1-9) is a competitive inhibitor of ACE; therefore, the administration of an ACEI increases Ang-(1-9) levels through being less catabolized by ACE; moreover, the inhibition of ACE leads to increased availability of Ang I substrate, which in turn is metabolized by ACE2 to Ang-(1-9). 51 The 

(A) Beta-adrenergic blockers. It has been demonstrated that betaadrenergic blockers reduced mortality rates in patients with septic shock. 54 Taking BB before hospitalization in patients with COVID-19 had significantly reduced dyspnea in these patients. 33 Betaadrenergic blockers negatively regulate renin release from juxtaglomerular cells in the kidneys through their inhibitory effect on the sympathetic system, and also by direct renin inhibition of agents such as aliskiren leading to renin depletion and decreased activity of the RAAS, Ang I, Ang II, and Ang-(1-7). 37, 55 Nebivolol, which is a beta-blocker, increases cardiac ACE2. 28 51 Carboxypeptidases convert bradykinin to (des-Arg9)-bradykinin, an agonist of the B1 receptor, which occurs after tissue injury. In addition, ACE2

degrades (des-Arg9)-BK. 51 There is a crosstalk between the RAAS and the kallikrein/kinin pathways as BK receptor signaling is augmented by Ang-(1-9). 35 Interaction between Ang-(1-7) and BK mostly occurs in blood vessels as Ang-(1-7) potentiates BK and also kinins mediate the vascular functions of Ang- (1-7) . Furthermore, all components of the kallikrein-kinin system are expressed in kidney, which exerts a paracrine influence on local nephron functions. This system produces local concentrations of BK in the kidneys much more than those that exist in the blood and modify the actions of Ang-(1-7). 5

It has been suggested that alteration in the HA synthesis and degrada- The RAAS plays an essential role in glucose homeostasis. It seems that ACE2 acts with a compensatory mechanism for hyperglycemiainduced RAAS activation and has protective role in diabetes. Since some antihyperglycemic medications such as insulin, peroxisome proliferator-activated receptor-γ agonist (pioglitazone), and glucagonlike peptide 1 (liraglutide) have both modulatory effects on the RAAS and anti-inflammatory effects and due to the anti-inflammatory effects of some of these agents in animal models with lung injury, it might be inferred that they can potentially be protective against COVID-19-induced lung injury. 39 4.9 | Janus-activated kinase inhibitors the RAAS and COVID-19

Angiotensin II activates the JAK2/STAT pathway that is critical for Ang II-induced hypertension development. Chronic blockade of JAK2 by its inhibitors has prevented Ang II-induced hypertension in animals. 58 Baricitinib is one of the proposed agents for COVID-19 treatment as an antiviral agent with anti-cytokine activity. The mechanism of reducing viral infection of host respiratory cells by baricitinib is through its high affinity inhibitory effect on numb-associated kinases such as AAK1, BIKE, and GAK kinases. Its anti-cytokine activity is through the inhibition of cytokine signaling. 41 Also, fedratinib, as a specific JAK2 inhibitor, has been suggested for the cytokine storm suppression in patients with severe COVID-19. 42 

Antioxidant, anti-inflammatory, and antiviral effects of resveratrol suggested this compound to be studied in the treatment of patients with COVID-19. Resveratrol suppresses Ang II that might decrease inflammation. Also, antioxidant effects of resveratrol in the lung might reduce lung damage. This compound is safe to use with maximum of 2 to 3 g daily. 43, 44, 59 However, its advantage in COVID-19 patients as an adjunct to other therapies should be studied. 

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None.

Providing Tables: Zohreh Rahimi