Accessibility / Report Error

Interactions amongst inflammation, renin-angiotensin-aldosterone and kallikrein-kinin systems: suggestive approaches for COVID-19 therapy

Abstract

Coronavirus disease 2019 (COVID-19) is a rapid-spread infectious disease caused by the SARS-CoV-2 virus, which can culminate in the renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin (KKS) systems imbalance, and in serious consequences for infected patients. This scoping review of published research exploring the RAAS and KKS was undertaken in order to trace the history of the discovery of both systems and their multiple interactions, discuss some aspects of the viral-cell interaction, including inflammation and the system imbalance triggered by SARS-CoV-2 infection, and their consequent disorders. Furthermore, we correlate the effects of continued use of the RAAS blockers in chronic diseases therapies with the virulence and physiopathology of COVID-19. We also approach the RAAS and KKS-related proposed potential therapies for treatment of COVID-19. In this way, we reinforce the importance of exploring both systems and the application of their components or their blockers in the treatment of coronavirus disease.

Keywords:
Renin-angiotensin-aldosterone system; Kallikrein-kinin system; COVID-19; SARS-associated coronavirus; Inflammation; Coronavirus

Background

SARS-CoV-2 is the virus responsible for the current devastating pandemic of coronavirus disease 2019 (COVID-19) [11. Chan JFW, Yuan S, Kok KH, To KKW, Chu H, Yang J, Xing F, Liu J, Yip CCY, Poon RW, Tsoi HW, Lo SKF, Chan KH, Poon VKM, Chan WM, Ip JD, Cai JP, Cheng VCC, Chen H, Hui CK, Yuen KY. A familial cluster of pneumonia associated with the 2019 novel Coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet . 2020 Feb 15;395(10223):514-23. -33. Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet. 2020 Feb 15;395(10223):470-3. ]. This disease was first reported in Wuhan (China) in late 2019 and has spread worldwide with a high transmission rate that made COVID-19 be characterized as a pandemic, the first caused by a coronavirus, on March 11, 2020 [44. World Health Organization (WHO) [Internet]. Geneva: WHO; -2021. WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020 [cited 2020 Jul 14]. Available from: Available from: https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020 .
https://www.who.int/director-general/spe...
]. Exceeding 5.0 million of deaths and 247 million of confirmed cases worldwide up to early November 2021, is inarguably that COVID-19 is the most challenging coronavirus outbreak in relation to the previous coronaviruses severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS) [33. Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet. 2020 Feb 15;395(10223):470-3. ,55. World Health Organization (WHO) [Internet]. Geneva: WHO ; -2021. Dashboard. [cited 2021 Nov 04]. Available from: Available from: https://covid19.who.int .
https://covid19.who.int...
].

COVID-19 was characterized as an acute respiratory disease that may turn into pneumonia with symptoms such as fever, cough and dyspnea, which can quickly progress to death. Multiple lines of evidence indicate that the COVID-19 pandemic has profound not only health effects, but also psychological, social and economic outcomes, which will probably persist for months and years to come [66. Sher L. The impact of the COVID-19 pandemic on suicide rates. QJM. 2020 Oct 1;113(10):707-12. ,77. Nicola M, Alsafi Z, Sohrabi C, Kerwan A, Al-Jabir A, Iosifidis C, Agha M, Agha R. The socio-economic implications of the coronavirus pandemic (COVID-19): a review. Int J Surg. 2020 Jun;78:185-93. ]. Given the impact of the pandemic, we summarized the available updates on the multidisciplinary approaches for the therapeutic strategies for COVID-19 related with the renin-angiotensin-aldosterone system (RAAS) and kallikrein-kinin system (KKS) components. They are systems that may work coordinately to regulate blood pressure and electrolyte homeostasis, whose deregulation is related to numerous diseases.

Methods

A scoping review with a thorough systematic search and screening process was developed based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) [88. Kastner M, Tricco AC, Soobiah C, Lillie E, Perrier L, Horsley T, Welch V, Cogo E, Antony J, Straus SE. What is the most appropriate knowledge synthesis method to conduct a review? Protocol for a scoping review. BMC Med Res Methodol. 2012 Aug 3;12:114. ,99. Tricco AC, Lillie E, Zarin W, O’Brien KK, Colquhoun H, Levac D, Moher D, Peters MDJ, Horsley T, Weeks L, Hempel S, Akl EA, Chang C, McGowan J, Stewart L, Hartling L, Aldcroft A, Wilson MG, Garritty C, Lewin S, Godfrey CM, Macdonald MT, Langlois EV, Soares-Weiser K, Moriarty J, Clifford T, Tunçalp Ö, Straus SE. PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Ann Intern Med. 2018 Oct 2;169(7):467-73. ]. The search was performed in the following databases: Medline/Pubmed, SciELO and Scopus from 1949 to October 2020 publications. The selection of the papers was performed in a standardized manner by two authors independently. Possible discrepancies were analyzed by the third author and the search strategy was reviewed by all authors.

The articles were eligible for inclusion when they (a) brought the history of the discovery of the RAAS and KKS, (b) reported the components of the systems, namely protein precursors, enzymes and peptides, (c) were mainly focused in the basic principles of physiology systems, mechanisms of the diseases in which they are involved and the relevant treatments and (d) explored the relationship of both systems with COVID-19 in addition to its main characteristics and symptoms. The reviewers selected the 125 publications, discussed the results and had a consensus on the screening of the literature and consistency of the analysis. The final search results were exported into Zotero and duplicates were removed by the author.

Our work does not assess the quality of included articles, but aims to provide a preliminary picture of what has been published in the literature about the correlation between COVID-19 and the RAAS and KKS.

Results

Renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone system is a cascade of hormones whose main function is to control blood pressure, through vasoconstriction in the smooth muscle of the vessels, and intravascular volume, in which there is a decrease in sodium excretion by the kidneys, mediated by aldosterone. There is a precursor, angiotensinogen, produced mainly in the liver, and in smaller amounts in several extrahepatic tissues, such as brain, heart and kidney. It is usually cleaved by renin, releasing angiotensin I (Ang I). In turn, this inactive decapeptide is processed by angiotensin I-converting enzyme (ACE), a dipeptidyl carboxypeptidase zinc-dependent releasing angiotensin II (Ang II), a peptide with important vasoconstrictive function. In addition, the ACE protease also participates in the metabolism of other peptides such as the conversion of angiotensin 1-7 (Ang 1-7) to angiotensin 1-5 (Ang 1-5), and also inactivates bradykinin (BK), a potent vasodilator of the KKS.

Ang II performs its main function by the angiotensin II receptors type 1 (AT1R) and type 2 (AT2R) activation, both of them belonging to the G protein-coupled receptor family. Most of the actions of Ang II are mediated by AT1R, such as promotion of hypertrophy, cellular proliferation and fibrosis. Both receptors are abundant in adults and are found mainly in vascular smooth muscle. However, in some pathological conditions, AT2 receptor shows an increased tissue expression and antagonizes the effects induced by AT1 receptor. The stimulation of AT2R provides vasodilation that can counterbalance the vasoconstrictor effects associated with the incitement of AT1 receptors.

Angiotensin converting enzyme 2 (ACE2), is a zinc metalloprotease that exists both as a membrane-associated form and as a secreted form, which is also known to regulate the RAAS. The name of ACE2 was given when it was discovered in 2000, because of considerable homology with ACE, 42% sequence identity and 61% sequence similarity. Moreover, ACE2 contains a single zinc-binding domain HEXXH, which is homologous to the active sites of ACE; however, it is not inhibited by ACE inhibitors [1010. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000 Sep 1;87(5):E1-9. ,1111. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000 Oct 27;275(43):33238-43. ].

In turn, ACE2 is able to cleave Ang I and II into angiotensin 1-9 (Ang 1-9) and Ang 1-7, respectively. Both are key elements related to cardiovascular protection, regulation of vascular tone, blood pressure, electrolyte balance and water intake [1010. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000 Sep 1;87(5):E1-9. ,1212. McKinney CA, Fattah C, Loughrey CM, Milligan G, Nicklin SA. Angiotensin-(1-7) and angiotensin-(1-9): function in cardiac and vascular remodelling. Clin Sci (Lond). 2014 Jun;126(12):815-27. ], in addition to the important role in inflammation and fibrosis [1313. Marshall RP, Gohlke P, Chambers RC, Howell DC, Bottoms SE, Unger T, McAnulty RJ, Laurent GJ. Angiotensin II and the fibroproliferative response to acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2004 Jan;286(1):L156-164. ]. In this sense, ACE2 plays an important role in heart failure, in diabetic microvascular or macrovascular diseases [1414. Soro-Paavonen A, Gordin D, Forsblom C, Rosengard-Barlund M, Waden J, Thorn L, Sandholm N, Thomas MC, Groop PH, FinnDiane Study Group. Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications. J Hypertens. 2012 Feb;30(2):375-83. ] and in inflammatory lung disease [1515. Zhang X, Zheng J, Yan Y, Ruan Z, Su Y, Wang J, Huang H, Zhang Y, Wang W, Gao J, Chi Y, Lu X, Liu Z. Angiotensin-converting enzyme 2 regulates autophagy in acute lung injury through AMPK/mTOR signaling. Arch Biochem Biophys. 2019 Sep 15;672:108061. ].

Ang 1-7, which binds to the Mas receptor, exerts many positive effects on the cardiovascular system (e.g. increased endothelial function, reduced fibrosis, anti-proliferative effects on smooth muscle cells and anti-cardiac hypertrophy), as well as on other organs, such as the lungs, it exerts anti-fibrotic, anti-inflammatory and anti-apoptotic effects [1616. Santos RAS, Simoes e Silva AC, Maric C, Silva DMR, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SVB, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8258-63. -1919. Wang W, Bodiga S, Das SK, Lo J, Patel V, Oudit GY. Role of ACE2 in diastolic and systolic heart failure. Heart Fail Rev. 2012 Sep;17(4-5):683-91. ]. Ang 1-7/Mas axisalso is related to reduction of proinflammatory cytokines and induction of IL-10, an important anti-inflammatory cytokine [2020. Jia H. Pulmonary angiotensin-converting enzyme 2 (ACE2) and inflammatory lung disease. Shock. 2016 Sep;46(3):239-48. ].

Another axis that is modulated by the action of ACE2, which also shows beneficial biological effects is Ang 1-9/AT2R, resulting in cardioprotective effects [2121. Flores-Muñoz M, Godinho BMDC, Almalik A, Nicklin SA. Adenoviral delivery of angiotensin-(1-7) or angiotensin-(1-9) inhibits cardiomyocyte hypertrophy via the mas or angiotensin type 2 receptor. PloS One. 2012;7(9):e45564. ,2222. Flores-Munoz M, Work LM, Douglas K, Denby L, Dominiczak AF, Graham D, Nicklin SA. Angiotensin-(1-9) attenuates cardiac fibrosis in the stroke-prone spontaneously hypertensive rat via the angiotensin type 2 receptor. Hypertension. 2012 Feb;59(2):300-7. ]. Moreover, ACE2 also cleaves a single-terminal residue from several others bioactive peptides including neurotensin, dynorphin A (1-13), apelin-13, and des-Arg9bradykinin, here named DABK [2323. Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, Godbout K, Parsons T, Baronas E, Hsieh F, Acton S, Patane M, Nichols A, Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002 Apr 26;277(17):14838-43. ,2424. Donoghue M, Wakimoto H, Maguire CT, Acton S, Hales P, Stagliano N, Fairchild-Huntress V, Xu J, Lorenz JN, Kadambi V, Berul CI, Breitbart RE. Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins. J Mol Cell Cardiol. 2003 Sep;35(9):1043-53. ]. Thus, the imbalance in ACE2 levels is closely related to heart failure, systemic and pulmonary hypertension, myocardial infarction, diabetic cardiovascular complications and gut dysbiosis [2525. Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ Res. 2016 Apr 15;118(8):1313-26. -2727. de Oliveira AP, Lopes ALF, Pacheco G, de Sá Guimarães Nolêto IR, Nicolau LAD, Medeiros JVR. Premises among SARS-CoV-2, dysbiosis and diarrhea: walking through the ACE2/mTOR/autophagy route. Med Hypotheses. 2020 Nov;144:110243. ].

Kallikrein-kinin system

The kallikrein-kinin system is a vasodilator system that also opposes the vasoconstrictor effects provided by the RAAS. The KKS is made up of kininogens, kallikreins (tissue and plasma), kinins, kininases and kinin-degrading enzymes.

There are two forms of kininogens, high and low molecular weight kininogens (HMWK and LMWK, respectively). This inactive precursor, is synthesized primarily in the liver, then is secreted and transported in plasma, and processed by proteolytic action of kallikreins. Kallikreins are derived from inactive precursors, pre-kallikreins, they are synthesized predominantly in the liver and activated through the Hageman's factor (factor XII). Due to the factor XII role in the KKS system, its modulation is linked to formations of thrombosis and fibrinolysis [2828. Revenko AS, Gao D, Crosby JR, Bhattacharjee G, Zhao C, May C, Gailani D, Monia BP, MacLeod AR. Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. Blood. 2011 Nov 10;118(19):5302-11. ,2929. Renné T, Schmaier AH, Nickel KF, Blombäck M, Maas C. In vivo roles of factor XII. Blood. 2012 Nov 22;120(22):4296-303. ].

It has been found that kallikrein exists in two different forms, plasma kallikrein, which cleaves HMWK into BK and tissue kallikrein, which processes LMWK into Lys-BK, known as kallidin. Through kallikreins, kininogen is cleaved generating kinins, biologically active peptides with vasodilatory actions, which can be processed by kininases, becoming inactive peptides.

Bradykinin, the main kinin, was discovered by a Brazilian scientist, Rocha e Silva, in the 1940s [3030. Rocha e Silva M, Beraldo WT, Rosenfeld G. Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin. Am J Physiol. 1949 Feb;156(2):261-73. ]. In a few years later, additional studies of Rocha e Silva, Ferreira and Vane revealed that certain peptides found in Bothrops jararaca snake venom potentiated the effects of BK by inhibiting its degradation especially in the lungs. Then, Ferreira discovered the bradykinin potentiating factor, BPF, it was the beginning of the inhibition of the angiotensin converting enzyme [3131. Ferreira SH, Rocha e Silva M. Potentiation of bradykinin and eledoisin by BPF (bradykinin potentiating factor) from Bothrops jararaca venom. Experientia. 1965 Jun 15;21(6):347-9. -3333. Ferreira SH. A bradykinin-potentiating factor (bpf) present in the venom of Bothrops jararca. Br J Pharmacol Chemother. 1965 Feb;24(1):163-9. ].

Based on BPF, scientists developed captopril (under the pharmaceutical name Capoten), that was the first oral angiotensin converting enzyme inhibitor and one of the most common therapies against arterial hypertension. It was considered a breakthrough because of its mechanism of action and its structure-based drug design [3434. Downey P. Profile of Sérgio Ferreira. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19035-7. ].

BK has the ability to increase vascular permeability and causes vasodilation of arteries and veins, in addition to having mechanisms that trigger the release of others mediators, such as nitric oxide in inflamed tissues [3535. Golias C, Charalabopoulos A, Stagikas D, Charalabopoulos K, Batistatou A. The kinin system--bradykinin: biological effects and clinical implications. Multiple role of the kinin system--bradykinin. Hippokratia. 2007 Jul;11(3):124-8. ]. BK is also a potent pain-producing agent and its action is enhanced by prostaglandins.

Other kinin product of the KKS is DABK, a stable and active BK metabolite originated by proteolytic action of carboxypeptidase M (CPM) and carboxypeptidase N (CPN), also known as kininase I. Increased DABK levels are responsible for increasing vascular permeability, thus promoting angioedema, and pro-inflammatory repercussions, which may be blocked by the action of ACE2, as this enzyme is able to degrade it [2323. Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, Godbout K, Parsons T, Baronas E, Hsieh F, Acton S, Patane M, Nichols A, Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002 Apr 26;277(17):14838-43. ].

Kinins act on target cells through receptors coupled to protein G, kinin B1 and B2 receptors (B1R and B2R). B2 receptor is the main mediator of BK and kallidin, while B1 receptor mediates the actions of DABK and des-Arg10 kallidin. The B2 receptor is constitutive and is expressed at a low level in healthy tissues, while B1R is widely distributed, and upregulated in tissue damage mediated by various pre-inflammatory cytokines. B1R and B2R activation induces vascular permeability [3636. Bossi F, Peerschke EI, Ghebrehiwet B, Tedesco F. Cross-talk between the complement and the kinin system in vascular permeability. Immunol Lett. 2011 Oct 30;140(1-2):7-13. ], as well as neutrophil recruitment, and thus contributes to the inflammatory state [3737. Mossberg M, Ståhl AL, Kahn R, Kristoffersson AC, Tati R, Heijl C, Segelmark M, Leeb-Lundberg LMF, Karpman D. C1-inhibitor decreases the release of vasculitis-like chemotactic endothelial microvesicles. J Am Soc Nephrol. 2017 Aug;28(8):2472-81. ].

Interactions between RAAS and KKS

The RAAS and KKS represent two systems with a wide range of physiological and pathophysiological actions, and play effects that are often opposite to each other. In the RAAS, the main function of ACE, is the conversion of Ang I to Ang II, but this enzyme, also known as kininase II, even is responsible for the degradation of BK, the main peptide formed by the KKS activation [3838. Yang HY, Erdös EG, Levin Y. A dipeptidyl carboxypeptidase that converts angiotensin I and inactivates bradykinin. Biochim Biophys Acta. 1970 Aug 21;214(2):374-6. ]. ACE converts BK into the thrombin-induced platelet aggregation-inhibitory peptide, bradykinin 1-5 [3939. Murphey LJ, Malave HA, Petro J, Biaggioni I, Byrne DW, Vaughan DE, Luther JM, Pretorius M, Brown NJ. Bradykinin and its metabolite bradykinin 1-5 inhibit thrombin-induced platelet aggregation in humans. J Pharmacol Exp Ther. 2006 Sep;318(3):1287-92. ,4040. Hasan AA, Amenta S, Schmaier AH. Bradykinin and its metabolite, Arg-Pro-Pro-Gly-Phe, are selective inhibitors of alpha-thrombin-induced platelet activation. Circulation. 1996 Aug 1;94(3):517-28. ]. In this way, ACE is the prior connection point between both systems, the RAAS and KKS, exerting important effects on kidney function modulators, as shown in Figure 1.

Figure 1
Pathways of interaction between the kallikrein-kinin and renin-angiotensin-aldosterone systems and mechanism of action of angiotensin converting enzyme (ACE) inhibitors (ACEI) and angiotensin type 1 (AT1) receptor blockers (ARB). Kininogen, the precursor of kallikrein-kinin system is cleaved by kallikrein-releasing bradykinin that acts mainly on B2R promoting the effects described in the box. Then, bradykinin is degraded by ACE or can be converted to DABK by CPM and CPN, DABK is an agonist of B1 receptor, subsequently ACE2 can inactivate DABK. In renin-angiotensin-aldosterone system, the precursor angiotensinogen is processed by renin-releasing angiotensin I, which can be cleaved by ACE to form angiotensin II that exerts its effects by binding to AT1 and AT2. Ang II is substrate for ACE2 generating angiotensin 1-7, an active peptide that exerts protective effects binding to Mas. ACEI acts by inhibiting ACE, consequently ACEIs inhibit Ang II formation and Ang 1-7 and BK degradation, these effects combined promote vasodilation. ARBs, blockers that act specifically on AT1R, inhibit Ang II binding to AT1R and its effects. Also, they possibly trigger intracellular acidification that can activate kallikrein and promote BK synthesis. B1R antagonists can block DABK-induced pro-inflammatory signaling. ACE: angiotensin-converting enzyme; ACEI: angiotensin-converting enzyme inhibitors; ACE2: angiotensin-converting enzyme 2; ARB: angiotensin II receptor blockers; B1R: kinin B1 receptor; CPM: carboxypeptidase M; CPN: carboxypeptidase N; DABK: des-Arg9 bradykinin.

Another RAAS enzyme that also plays an important role in the KKS is ACE2. Although it is unable to cleave BK, ACE2 has its metabolite as substrate, DABK. Sodhi et al. [4141. Sodhi CP, Wohlford-Lenane C, Yamaguchi Y, Prindle T, Fulton WB, Wang S, McCray Jr PB, Chappell M, Hackam DJ, Jia H. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J Physiol Lung Cell Mol Physiol. 2018 Jan 1;314(1):L17-31. ] provided the first evidence that DABK is a substrate of pulmonary ACE2 in vivo and the attenuation of ACE2 activity leads to decrease of DABK inactivation. Consequently, improves DABK/B1R signaling, which releases proinflammatory chemokines from airway epithelia, promotes neutrophil infiltration, and exaggerated lung inflammation and injury [4141. Sodhi CP, Wohlford-Lenane C, Yamaguchi Y, Prindle T, Fulton WB, Wang S, McCray Jr PB, Chappell M, Hackam DJ, Jia H. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J Physiol Lung Cell Mol Physiol. 2018 Jan 1;314(1):L17-31. ].

Concerning renin, the first enzyme responsible for cascade RAAS activation, it is obtained from prorenin processing, and it can be activated by proteolytic action, from removal its propeptide, or by non-proteolytic way, which involves conformational arrangements induced by exposure to low pH and cold [4242. Pitarresi TM, Rubattu S, Heinrikson R, Sealey JE. Reversible cryoactivation of recombinant human prorenin. J Biol Chem. 1992 Jun 15;267(17):11753-9. ,4343. Suzuki F, Hayakawa M, Nakagawa T, Nasir UM, Ebihara A, Iwasawa A, Ishida Y, Nakamura Y, Murakami K. Human prorenin has “gate and handle” regions for its non-proteolytic activation. J Biol Chem. 2003 Jun 20;278(25):22217-22. ]. Trypsin and plasmin, as well as tissue and plasma kallikreins can all correctly process prorenin in vitro [4444. Kikkawa Y, Yamanaka N, Tada J, Kanamori N, Tsumura K, Hosoi K. Prorenin processing and restricted endoproteolysis by mouse tissue kallikrein family enzymes (mK1, mK9, mK13, and mK22). Biochim Biophys Acta. 1998 Jan 15;1382(1):55-64. -4646. Sealey JE, Atlas SA, Laragh JH, Oza NB, Ryan JW. Human urinary kallikrein converts inactive to active renin and is a possible physiological activator of renin. Nature. 1978 Set 14;275(5676):144-5. ]. Kallikrein is generated from pre-kallikrein in plasma after destruction of the natural inhibitors of contact activation, by exposure to low pH or low temperature, and probably serves as a prorenin-activating enzyme [4646. Sealey JE, Atlas SA, Laragh JH, Oza NB, Ryan JW. Human urinary kallikrein converts inactive to active renin and is a possible physiological activator of renin. Nature. 1978 Set 14;275(5676):144-5. ,4747. Derkx FH, Tan-Tjiong HL, Man in ’t Veld AJ, Schalekamp MP, Schalekamp MA. Activation of inactive plasma renin by plasma and tissue kallikreins. Clin Sci (Lond). 1979 Oct;57(4):351-7. ], another connection point between the RAAS and KKS systems.

Although there are no compelling evidences for in vivo prorenin activation by kallikrein, some studies indicate a correlation between kallikrein variables or levels with active plasma renin [4848. Leckie BJ, Morton JJ. Relation between renin and prorenin in plasma from hypertensive patients and normal people: evidence for different renin:prorenin ratios. J Hum Hypertens. 1995 Jun;9(6):493-6. -5050. Biswas N, Maihofer AX, Mir SA, Rao F, Zhang K, Khandrika S, Mahata M, Friese RS, Hightower CM, Mahata SK, Baker DG, Nievergelt CM, Vaingankar SM, O'Connor DT. Polymorphisms at the F12 and KLKB1 loci have significant trait association with activation of the renin-angiotensin system. BMC Med Genet. 2016 Mar 11;17:21. ]. Lieb et al. [5151. Lieb W, Chen MH, Teumer A, de Boer RA, Lin H, Fox ER, Musani SK, Wilson JG, Wang TJ, Völzke H, Petersen AK, Meisinger C, Nauck M, Schlesinger S, Li Y, Menard J, Hercberg S, Wichmann HE, Völker U, Rawal R, Bidlingmaier M, Hannemann A, Dörr M, Rettig R, van Gilst WH, van Veldhuisen DJ, Bakker SJ, Navis G, Wallaschofski H, Meneton P, van der Harst P, Reincke M, Vasan RS, CKDGen Consortium, ICBP, EchoGen Consortium. Genome-wide meta-analyses of plasma renin activity and concentration reveal association with the kininogen 1 and prekallikrein genes. Circ Cardiovasc Genet. 2015 Feb;8(1):131-40. ] performed a meta-analysis from cohorts of European and European-American ancestry and found association between plasma renin activity and concentration with kininogen and pre-kallikrein genes. Their data add support to this concept by indicating that genetic variation in the KKS components influence interindividual variation of plasma renin activity [5151. Lieb W, Chen MH, Teumer A, de Boer RA, Lin H, Fox ER, Musani SK, Wilson JG, Wang TJ, Völzke H, Petersen AK, Meisinger C, Nauck M, Schlesinger S, Li Y, Menard J, Hercberg S, Wichmann HE, Völker U, Rawal R, Bidlingmaier M, Hannemann A, Dörr M, Rettig R, van Gilst WH, van Veldhuisen DJ, Bakker SJ, Navis G, Wallaschofski H, Meneton P, van der Harst P, Reincke M, Vasan RS, CKDGen Consortium, ICBP, EchoGen Consortium. Genome-wide meta-analyses of plasma renin activity and concentration reveal association with the kininogen 1 and prekallikrein genes. Circ Cardiovasc Genet. 2015 Feb;8(1):131-40. ].

Another factor that can modulate renin is the stimulation of B2R by BK, that induces renin synthesis and releasing, by collecting duct cells, through protein kinase C stimulation and nitric oxide release [5252. Lara LS, Bourgeois CRT, El-Dahr SS, Prieto MC. Bradykinin/B2 receptor activation regulates renin in M-1 cells via protein kinase C and nitric oxide. Physiol Rep. 2017 Apr;5(7):e13211. ].In addition, PGE2 (prostaglandin E2), a product of BK stimulation, was described for releasing renin, mediated by EP2 and EP4 receptors in mouse kidneys[5353. Schweda F, Klar J, Narumiya S, Nüsing RM, Kurtz A. Stimulation of renin release by prostaglandin E2 is mediated by EP2 and EP4 receptors in mouse kidneys. Am J Physiol Renal Physiol. 2004 Sep;287(3):F427-33. ],which support further the interactions between the RAAS and KKS.

Ang 1-7, which has augmented levels with increased levels of ACE2 or Ang I, can also improve BK effects. In addition to inhibiting ACE activity by binding to its active site, independently of blocking ligand hydrolysis, Ang 1-7 also is able to potentiate B2 receptor through direct or indirect interaction of its receptor with B2R after peptide stimulation [5454. Deddish PA, Marcic B, Jackman HL, Wang HZ, Skidgel RA, Erdös EG. N-domain-specific substrate and C-domain inhibitors of angiotensin-converting enzyme: angiotensin-(1-7) and keto-ACE. Hypertension. 1998 Apr;31(4):912-7. ,5555. Tschöpe C, Schultheiss HP, Walther T. Multiple interactions between the renin-angiotensin and the kallikrein-kinin systems: role of ACE inhibition and AT1 receptor blockade. J Cardiovasc Pharmacol. 2002 Apr;39(4):478-87. ].

Moreover, B2R forms dimers with several RAAS receptors that are important for several physiologic functions, including thrombosis risk regulation. The B2R also complexes with endothelial cell nitric oxide synthase (eNOS, NOS3), while B1R couples with cytokine‐inducible nitric oxide synthase (iNOS, NOS2) [5656. Schmaier AH. The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. J Thromb Haemost. 2016 Jan;14(1):28-39. ].

Recently, it was demonstrated that Ang II-mediated effects on neuroinflammation and oxidative stress are mediated by the stimulation of B1R, and its blockade prevents such effects in neurons in mouse neuronal cultures [5757. Parekh RU, Robidoux J, Sriramula S. Kinin B1 Receptor blockade prevents angiotensin ii-induced neuroinflammation and oxidative stress in primary hypothalamic neurons. Cell Mol Neurobiol. 2020 Jul;40(5):845-57. ].

Although the relationship between angiotensin II receptors and the KKS has been poorly studied, it has been shown that stimulation of the AT2R by Ang II causes intracellular acidification. Since acidification is known to increase kininogenase activity, it is possible that AT2R mediates intracellular acidification and kallikrein activation, resulting in the KKS stimulation via BK releasing [5858. Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, Miyazaki M, Nozawa Y, Ozono R, Nakagawa K, Miwa T, Kawada N, Mori Y, Shibasaki Y, Tanaka Y, Fujiyama S, Koyama Y, Fujiyama A, Takahashi H, Iwasaka T. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest. 1999 Oct;104(7):925-35. ].

Coronavirus disease 2019 (COVID-19)

Besides ACE2 had distinct roles ranging from catalytic activities with various substrates to amino acid transporter, ACE2 also plays an important role as a receptor on severe acute respiratory syndrome (SARS) coronaviruses [5959. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003 Nov 27;426(6965):450-4. -6363. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 27;367(6485):1444-8. ]. SARS-CoV-2 transmission occurs through different routes (that is, fomites, air or fecal-oral route) from animal to human and human to human. COVID-19 has shown a wide variety of expression and severity of symptoms, from very mild or nonexistent symptoms to flu-like symptoms and, in more severe cases, pneumonia, severe acute respiratory syndrome and even death [6464. Lopera Maya EA, van der Graaf A, Lanting P, van der Geest M, Fu J, Swertz M, Franke L, Wijmenga C, Deelen P, Zhernakova A, Sanna S; Lifelines Cohort Study. Lack of association between genetic variants at ACE2 and TMPRSS2 genes involved in SARS-CoV-2 infection and human quantitative phenotypes. Front Genet. 2020 Jun 8;11:613. ].

In addition to the occurrence of acute injury and loss of renal function, chronic damage to the cardiovascular system is an important clinical complication of viral infection and is associated with increased rates of mortality and morbidity in these patients [6565. Moitinho MS, Belasco AGS, Barbosa DA, Fonseca CD. Acute kidney injury by SARS-CoV-2 virus in patients with COVID-19: an integrative review. Rev Bras Enferm. 2020;73 Suppl 2:e20200354. ,6666. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020 May;17(5):259-60. ]. Manifestations of COVID-19 include other organs with symptoms at the digestive tract, sensory perceptions and at the central nervous system.

A critical literature review suggests that the severity of SARS-CoV-2 infection is also associated with loss of the immune regulation between protective and altered responses due to exacerbation of the inflammatory components, which in turn inhibits the development of protective immunity to the infection [6767. Manjili RH, Zarei M, Habibi M, Manjili MH. COVID-19 as an acute inflammatory disease. J Immunol. 2020 Jul 1;205(1):12-9. ]. Such dysregulated inflammation results in a cytokine storm that is evident in sepsis as well as in patients with severe respiratory diseases caused by coronaviruses such as SARS-CoV, MERS-CoV and SARS-CoV-2 [6868. Vaninov N. In the eye of the COVID-19 cytokine storm. Nat Rev Immunol. 2020 May;20(5):277. ,6969. Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017 Jul;39:517-28. ]. In an observational study with patients with severe COVID-19 symptoms it was related exacerbated systemic inflammation and signs of T cells exhaustion [7070. García LF. Immune response, inflammation, and the clinical spectrum of COVID-19. Front Immunol. 2020 Jun 16;11:1441. ].

The causes for these variations in disease severity are probably multifactorial, encompassing complex factors such as the expression of key components in different organs, patient health conditions, in addition to genetic factors.

The new coronavirus depends on two human proteins: ACE2, as a human receptor for virus invasion in the host cell, through interaction with viral S protein (Spike protein); and TMPRSS2, a serine protease which is responsible for the correct priming of S protein [6363. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 27;367(6485):1444-8. ]. It is known that an efficient interaction of viral S protein with human ACE2 a critical step in the replication cycle and it requires a certain level of affinity between the molecules. Furthermore, the efficiency of viral infection is strongly dependent on this process.

In this sense, Ortega et al. [7171. Ortega JT, Serrano ML, Pujol FH, Rangel HR. Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: an in silico analysis. EXCLI J. 2020 Mar 18;19:410-7. ] suggest that mutations in the viral S protein sequence might be favoring human to human transmission. They observed changes that triggered significant effects on SARS-CoV-2 spike/ACE2 interaction and reduced the binding energy, compared to Bat-CoV spike/ACE2 interaction [7171. Ortega JT, Serrano ML, Pujol FH, Rangel HR. Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: an in silico analysis. EXCLI J. 2020 Mar 18;19:410-7. ]. Therefore, specific changes, in the nature of residues or in the type of chemical interactions occurring between ligand and receptor, may be decisive. As it generates an improvement in this affinity, or even destabilize such interaction, which might play an imperative role in the differences in susceptibility to the disease and its symptoms.

It was reported that SARS-CoV-2 is able to bind to alveolar pneumocytes, which express ACE2 on its surface [7272. Carsana L, Sonzogni A, Nasr A, Rossi RS, Pellegrinelli A, Zerbi P, Rech R, Colombo R, Antinori S, Corbellino M, Galli M, Catena E, Tosoni A, Gianatti A, Nebuloni M. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study. Lancet Infect Dis. 2020 Oct;20(10):1135-40. ]. However, ACE2 mRNA is also found in a much broader distribution, including upper airways, heart, blood vessels, kidneys, liver, testis, gastrointestinal tract and eyes, which opens up the possibility of this virus infecting others tissues than the lung [1010. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000 Sep 1;87(5):E1-9. ,7373. Zhou L, Xu Z, Castiglione GM, Soiberman US, Eberhart CG, Duh EJ. ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection. Ocul Surf. 2020 Oct;18(4):537-44. -7575. Spak E, Hallersund P, Edebo A, Casselbrant A, Fändriks L. The human duodenal mucosa harbors all components for a local renin angiotensin system. Clin Sci (Lond). 2019 Apr 29;133(8):971-82. ]. In severe conditions of COVID-19, the presence of the viral receptor in these others tissues may explain the failure of several organs occasionally described in clinical studies. Therefore, it is not surprising that the initial reports have suggested that hypertension, diabetes, cerebrovascular and coronary heart diseases are the most frequent comorbidities in COVID-19 [7676. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Apr;8(4):e21. ,7777. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 May;8(5):475-81. ].

The difference in responses to SARS-CoV-2 infection between different individuals and countries can also be explained by the decreased immune response in the elderly, the presence of comorbidities or smoking habits [7878. Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM, Liu XQ, Chen RC, Tang CL, Wang T, Ou CQ, Li L, Chen PY, Sang L, Wang W, Li JF, Li CC, Ou LM, Cheng B, Xiong S, Ni ZY, Xiang J, Hu Y, Liu L, Shan H, Lei CL, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Cheng LL, Ye F, Li SY, Zheng JP, Zhang NF, Zhong NS, He JX, China Medical Treatment Expert Group for COVID-19. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. Eur Respir J. 2020 May 14;55(5):2000547. ]. However, severe cases of COVID-19 have been observed in young people, apparently without risk factors, as well. It indicates that most of the factors that explain the severity of the disease are still unknown.

The role of RAAS and KKS in COVID-19

The correlation between the RAAS and KKS with COVID-19 pathogenesis is suggested by several clinical features and symptoms observed in patients, given the close interconnection between both systems. While the RAAS controls vasoconstriction and vasodilation, the KKS regulates vasodilation and vascular permeability, which are also important in COVID-19.

It is known that the virus survival strategy is to elude and suppress host innate immune defenses through gene deactivation or inhibition [5959. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003 Nov 27;426(6965):450-4. ,7979. Ni G, Ma Z, Damania B. cGAS and STING: at the intersection of DNA and RNA virus-sensing networks. PLoS Pathog. 2018 Aug 16;14(8):e1007148. ]. In line, in coronaviruses as SARS-CoV, studies were observed a viral nonstructural protein (nsp1) binding to ribosomes and inhibiting host gene translation, a marked downregulation of ACE2 expression and inducing of ACE2 shedding from the cell surface [8080. Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM, Butany J. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest. 2009 Jul;39(7):618-25. -8282. Haga S, Nagata N, Okamura T, Yamamoto N, Sata T, Yamamoto N, Sasazuki T, Ishizaka Y. TACE antagonists blocking ACE2 shedding caused by the spike protein of SARS-CoV are candidate antiviral compounds. Antiviral Res. 2010 Mar;85(3):551-5. ].

Due to the important pathophysiological role of ACE2, Samavati and Uhal [8383. Samavati L, Uhal BD. ACE2, much more than just a receptor for SARS-COV-2. Front Cell Infect Microbiol. 2020 Jun 5;10:317. ] state that the binding of the viral spike to ACE2 triggers a potential effect on the loss of the protective effect of the ACE2/ Ang 1-7/ Mas pathway on alveolar epithelial cells and other organs, in addition to causing increased levels of Ang II, which can amplify the systemic deleterious effects of the RAAS in the patients [8383. Samavati L, Uhal BD. ACE2, much more than just a receptor for SARS-COV-2. Front Cell Infect Microbiol. 2020 Jun 5;10:317. ]. Although ACE2 allows viral entry at the epithelial surface, the ACE2/Ang 1-7/Mas axis can represent a potential target for therapeutic intervention, due to its role in protection in acute lung injury.

Compared to women, men with COVID-19 have more severe disease and higher mortality [8484. Xie J, Tong Z, Guan X, Du B, Qiu H. Clinical characteristics of patients who died of coronavirus disease 2019 in China. JAMA Netw Open. 2020 Apr 1;3(4):e205619. ,8585. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS, China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-20. ], it can be explained by several risk factors that are more frequent in men. Such as higher rates of preexisting comorbidities associated with COVID-19, as ischemic heart disease, hypertension, diabetes, chronic renal disease and cancer within 5 years, higher risk behaviors, as smoking and alcohol use, social isolation and certain occupational exposures; and lower innate immune response [8686. Sharma G, Volgman AS, Michos ED. Sex differences in mortality from COVID-19 pandemic: are men vulnerable and women protected? JACC Case Rep. 2020 Jul 15;2(9):1407-10. ].Regarding the difference in ACE2 levels between genders, the ACE2 gene is located on the X chromosome and the testis have much higher levels of ACE2 than the ovaries, which also suggests that women might have higher ACE2 levels and thus be protected against more severe disease compared to men [8787. Bhatia K, Zimmerman MA, Sullivan JC. Sex differences in angiotensin-converting enzyme modulation of Ang (1-7) levels in normotensive WKY rats. Am J Hypertens. 2013 May;26(5):591-8. ,8888. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res. 2020 May 1;116(6):1097-100. ].

In vivo, the enzyme that mediates the shedding of ACE2 ectodomain is ADAM-17 (A- disintegrin and metalloproteinase 17), also known as TACE (TNF-(-converting enzyme) due to its role to driven tumor necrosis factor-( (TNF-() extracellular domain shedding and activation, a cytokine implicated in chronic inflammation [8989. Lambert DW, Yarski M, Warner FJ, Thornhill P, Parkin ET, Smith AI, Hooper NM, Turner AJ. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem. 2005 Aug 26;280(34):30113-9. ,9090. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature. 1997 Feb 20;385(6618):729-33. ]. In addition, ADAM 17 is related to the processing of other cytokines and receptors, among which many are correlated with the initiation and exacerbation of inflammatory process [9191. Gooz M. ADAM-17: the enzyme that does it all. Crit Rev Biochem Mol Biol. 2010 Apr;45(2):146-69. ].

After the binding of SARS-CoV-2 to ACE2, the complex is internalized by endocytosis and ACE2 shedding is induced, consequently, the diminished ACE2 availability impairs directly the protective roles of ACE2/Ang 1-7/Mas and Ang 1-9/AT2R axes. In turn, the increase in Ang II levels activates the AT1 receptor, the overactivation of this signaling induces deleterious actions as progression of cardiovascular diseases, end-organs injury, cell growth, vascular contraction, fibrosis, inflammatory responses and salt and water retention, which undoubtedly, on its own, impairs the health of the infected patient [9292. Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, Raizada MK, Grant MB, Oudit GY. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res. 2020 May 8;126(10):1456-74. ].

Furthermore, other consequence of increased signaling via AT1R, is the activation of ADAM-17, which triggers the TNF-( releasing into extracellular region. In addition to the systemic cytokines, released due to SARS-CoV-2 infection, it can lead cytokine storm, besides to result in loss of ACE2 at the membrane due to its shedding function, leading a RAAS positive feedback cycle [9292. Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, Raizada MK, Grant MB, Oudit GY. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res. 2020 May 8;126(10):1456-74. -9494. Xu J, Sriramula S, Xia H, Moreno-Walton L, Culicchia F, Domenig O, Poglitsch M, Lazartigues E. Clinical relevance and role of neuronal AT1 receptors in ADAM17-mediated ACE2 shedding in neurogenic hypertension. Circ Res. 2017 Jun 23;121(1):43-55. ].

Regarding the KKS, Nicolau et al. [9595. Nicolau LAD, Magalhães PJC, Vale ML. What would Sérgio Ferreira say to your physician in this war against COVID-19: how about kallikrein/kinin system? Med Hypotheses. 2020 Oct;143:109886. ] was the first group that linked bradykinin to COVID-19 context, correlating it with Sérgio Ferreira's contributions from basic science to clinical ambit and this system. They hypothesized that targeting the KKS may be beneficial in SARS-CoV-2 infection, especially on early stages [9595. Nicolau LAD, Magalhães PJC, Vale ML. What would Sérgio Ferreira say to your physician in this war against COVID-19: how about kallikrein/kinin system? Med Hypotheses. 2020 Oct;143:109886. ].

The interaction of kinins to their respective receptors will increase the activation of eNOS and iNOS. It ensues nitric oxide and prostacyclin (PGI2) releasing along with pro-inflammatory cytokines/chemokines responsible for acute inflammation, which cause vasodilation, pain, cell proliferation and fibrosis [9696. Kuhr F, Lowry J, Zhang Y, Brovkovych V, Skidgel RA. Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors. Neuropeptides. 2010 Apr;44(2):145-54. ,9797. Tsai YJ, Hao SP, Chen CL, Lin BJ, Wu WB. Involvement of B2 receptor in bradykinin-induced proliferation and proinflammatory effects in human nasal mucosa-derived fibroblasts isolated from chronic rhinosinusitis patients. PloS One. 2015 May 13;10(5):e0126853. ], typical symptoms of COVID-19.

A common feature for many patients that get severe COVID-19 is serious lung damage caused by an overly vigorous immune response. It is characterized by the production of numerous inflammatory cytokines, the consequent cytokine storm. Ferreira et al. [9898. Ferreira SH, Lorenzetti BB, Poole S. Bradykinin initiates cytokine-mediated inflammatory hyperalgesia. Br J Pharmacol. 1993 Nov;110(3):1227-31. ] demonstrated that BK production is an important step in the activation of a cascade of cytokines that participate in the inflammatory hyperalgesia [9898. Ferreira SH, Lorenzetti BB, Poole S. Bradykinin initiates cytokine-mediated inflammatory hyperalgesia. Br J Pharmacol. 1993 Nov;110(3):1227-31. ].

COVID-19 patients can present with pulmonary edema early as symptom of the viral infection. Van de Veerdonk et al. [9999. van de Veerdonk FL, Netea MG, van Deuren M, van der Meer JW, de Mast Q, Brüggemann RJ, van der Hoeven H. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife. 2020 Apr 27;9:e57555. ,100100. van de Veerdonk F, Netea MG, van Deuren M, van der Meer JWM, de Mast Q, Bruggemann RJ,van der Hoeven H. Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach. Preprints. 2020 Apr 3[cited 2020 Oct 4]. Available from: Available from: https://www.preprints.org/manuscript/202004.0023/v1 .
https://www.preprints.org/manuscript/202...
] proposed that this disorder is caused by a local vascular problem due to activation of KKS receptors in lung endothelial cells. Since the coronavirus blocks ACE2 proteolytic activity for cell infection, the enzyme is unable to inactivate DABK, the potent ligand of B1R. Under this condition the lung environment is prone for a kinin-dependent local vascular leakage leading to angioedema via B1R and eventually B2R. Since this disorder is resistant to corticosteroids or adrenaline, this is an important feature of COVID-19 [9999. van de Veerdonk FL, Netea MG, van Deuren M, van der Meer JW, de Mast Q, Brüggemann RJ, van der Hoeven H. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife. 2020 Apr 27;9:e57555. ,100100. van de Veerdonk F, Netea MG, van Deuren M, van der Meer JWM, de Mast Q, Bruggemann RJ,van der Hoeven H. Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach. Preprints. 2020 Apr 3[cited 2020 Oct 4]. Available from: Available from: https://www.preprints.org/manuscript/202004.0023/v1 .
https://www.preprints.org/manuscript/202...
].

KKS appears to be involved in vascular leakage and inflammatory response observed during different viral infections [101101. Oehmcke-Hecht S, Köhler J. Interaction of the human contact system with pathogens-an update. Front Immunol. 2018 Feb 26;9:312. ]. Another symptom that has been highlighted in patients with COVID-19 and seems to be involved with this system is the formation of microthrombi, which can trigger thrombosis [102102. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers D, Kant KM, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res. 2020 Jul;191:148-50. ]. Since kallikrein, additionally, causes imbalance of coagulation system by activating factor XII and plasmin, the two mechanisms contribute to the formation of intravascular microthrombi, observed mainly in the lung tissue [9595. Nicolau LAD, Magalhães PJC, Vale ML. What would Sérgio Ferreira say to your physician in this war against COVID-19: how about kallikrein/kinin system? Med Hypotheses. 2020 Oct;143:109886. ].

RAAS blockers and related COVID-19 therapies

RAAS blockers, as ACE inhibitors (ACEI) and angiotensin II receptor blockers (ARBs), are worldwide used for effectively reducing systemic vascular resistance in patients with hypertension, heart failure and chronic renal disease. There are animal models studies that demonstrated a substantial increase of ACE2 expression under ACE inhibitors or ARBs administration, which represents a potential mechanistic link between SARS-CoV-2 infection and these medications [103103. Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, Diz DI, Gallagher PE. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005 May 24;111(20):2605-10. -105105. Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res. 2017 Nov;125(Pt A):21-38. ].

ACEI group (such as enalapril, ramipril, captopril, and lisinopril) acts by inhibiting ACE, making it unable to convert Ang I into Ang II, thus blocking vasoconstrictor properties, the activation of aldosterone and sodium reabsorption attributed to Ang II of the RAAS. In addition, the ACEI inhibits the conversion of active kinins (such as bradykinin and kallidin) in inactive peptides, promoting the vasodilating effect of the KKS cascade.

Evidences suggest that ACEI can also abolish the desensitization of the B2R or delay its sequestration, which also potentiates BK action [106106. Erdös EG, Marcic BM. Kinins, receptors, kininases and inhibitors--where did they lead us? Biol Chem. 2001 Jan;382(1):43-7. ]. Another effect of ACEI on KKS receptors was demonstrated by Ignjatovic et al. [107107. Ignjatovic T, Tan F, Brovkovych V, Skidgel RA, Erdös EG. Novel mode of action of angiotensin I converting enzyme inhibitors: direct activation of bradykinin B1 receptor. J Biol Chem. 2002 May 10;277(19):16847-52. ], they found that enalaprilat activates B1R directly in the absence of ACE. This inhibitor activates at the zinc-binding consensus sequence HEXXH in B1 receptor, which is present also in ACE but not in B2R [107107. Ignjatovic T, Tan F, Brovkovych V, Skidgel RA, Erdös EG. Novel mode of action of angiotensin I converting enzyme inhibitors: direct activation of bradykinin B1 receptor. J Biol Chem. 2002 May 10;277(19):16847-52. ].

While the ARB group (such as losartan, candesartan, valsartan, irbesartan, and telmisartan) blocks the AT1R. This blockade leads to increased Ang II levels, which stimulates the non-blocked angiotensin II receptor, AT2R, and triggers intracellular acidification by inhibiting the amiloride-sensitive Na+/H+ exchanger.

Consequently, it is possible that this condition activates kallikrein, resulting in augmented BK production and endothelial B2R stimulation through a paracrine mechanism, activating the NO/cGMP system and causing vasodilation [5555. Tschöpe C, Schultheiss HP, Walther T. Multiple interactions between the renin-angiotensin and the kallikrein-kinin systems: role of ACE inhibition and AT1 receptor blockade. J Cardiovasc Pharmacol. 2002 Apr;39(4):478-87. ,5858. Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, Miyazaki M, Nozawa Y, Ozono R, Nakagawa K, Miwa T, Kawada N, Mori Y, Shibasaki Y, Tanaka Y, Fujiyama S, Koyama Y, Fujiyama A, Takahashi H, Iwasaka T. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest. 1999 Oct;104(7):925-35. ]. Therefore, in addition to blocking the classical harmful effects of Ang II through AT1R signaling, therapies that use ARBs also promote the beneficial effects of the KKS, even indirectly by kallikrein activation.

The RAAS blockers have been extensively used to treat cardiovascular disorders, reducing mortality and morbidity. Thus, researches on SARS-CoV-2 pathogenesis have been focused on discussions about these compounds, and how they could fit pathophysiological processes of COVID-19, since these pathways were substantially studied in SARS-CoV [7676. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Apr;8(4):e21. ,108108. Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? Clin Sci (Lond). 2020 Mar 13;134(5):543-5. ]. Due to the increased ACE2 expression caused by treatment with these popularly used classes of drugs in some experimental models and high number of infected hypertensive patients, questions such as whether continued use of RAAS blockers could increase virulence and severity of symptoms or whether such treatment should be stopped, have been frequently asked.

The relationship between hypertension and COVID-19 mortality exists, but it is known that older ages strongly correlate with hypertension and have been associated with higher mortality rates from COVID-19 [8585. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS, China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-20. ,109109. Santesmasses D, Castro JP, Zenin AA, Shindyapina AV, Gerashchenko MV, Zhang B, Kerepesi C, Yim SH, Fedichev PO, Gladyshev VN. COVID-19 is an emergent disease of aging. Aging Cell. 2020 Oct;19(10):e13230. ]. Thus, new analyses need to be done aiming an adjustment with age-stratified data for the hypertension and mortality association, to verify if this is a reliable finding [110110. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-62. ].

Evidences also supports the possibility that ACEIs and/or ARBs could reduce the severity of COVID-19 infection, since ACEI and/or ARB treatment could diminish effects of Ang II and increase Ang 1-7 effects, leading to attenuated inflammation and fibrosis [111111. Sparks MA, South A, Welling P, Luther JM, Cohen J, Byrd JB, Burrell LM, Batlle D, Tomlinson L, Bhalla V, Rheault MN, Soler MJ, Swaminathan S, Hiremath S. Sound science before quick judgement regarding RAS blockade in COVID-19. Clin J Am Soc Nephrol. 2020 May 7;15(5):714-6. ]. Some studies, with animal models, support the idea that RAAS blockers use could be protective in conditions of viral pneumonia, including coronavirus infection [112112. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005 Aug;11(8):875-9. ,113113. Yang P, Gu H, Zhao Z, Wang W, Cao B, Lai C, Yang X, Zhang L, Duan Y, Zhang S, Chen W, Zhen W, Cai M, Penninger JM, Jiang C, Wang X. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep. 2014 Nov 13;4:7027. ]. In addition, a recent retrospective observational study from Wuhan linked the ACEIs/ARBs treatment of hypertensive subjects affected by SARS-CoV-2 with lower all-cause mortality [114114. Zhang P, Zhu L, Cai J, Lei F, Qin JJ, Xie J, Liu YM, Zhao YC, Huang X, Lin L, Xia M, Chen MM, Cheng X, Zhang X, Guo D, Peng Y, Ji YX, Chen J, She ZG, Wang Y, Xu Q, Tan R, Wang H, Lin J, Luo P, Fu S, Cai H, Ye P, Xiao B, Mao W, Liu L, Yan Y, Liu M, Chen M, Zhang XJ, Wang X, Touyz RM, Xia J, Zhang BH, Huang X, Yuan Y, Loomba R, Liu PP, Li H. Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020 Jun 5;126(12):1671-81. ].

Interrupting ACE inhibitors and ARBs treatments in asymptomatic and stable patients with heart failure, kidney disease, diabetes or hypertension will disrupt clinical care and strongly require additional medical visits [111111. Sparks MA, South A, Welling P, Luther JM, Cohen J, Byrd JB, Burrell LM, Batlle D, Tomlinson L, Bhalla V, Rheault MN, Soler MJ, Swaminathan S, Hiremath S. Sound science before quick judgement regarding RAS blockade in COVID-19. Clin J Am Soc Nephrol. 2020 May 7;15(5):714-6. ]. However, this decision is not feasible in this pandemic context, given the recommendations of social isolation and overcrowded hospitals.

Taking into account chronic patients using ACEI/ARBs, who were infected by SARS-CoV-2, the medical community substantially recommends they should not discontinue the treatment, neither temporarily [111111. Sparks MA, South A, Welling P, Luther JM, Cohen J, Byrd JB, Burrell LM, Batlle D, Tomlinson L, Bhalla V, Rheault MN, Soler MJ, Swaminathan S, Hiremath S. Sound science before quick judgement regarding RAS blockade in COVID-19. Clin J Am Soc Nephrol. 2020 May 7;15(5):714-6. ,115115. Aleksova A, Ferro F, Gagno G, Cappelletto C, Santon D, Rossi M, Ippolito G, Zumla A, Beltrami AP, Sinagra G. COVID-19 and renin-angiotensin system inhibition: role of angiotensin converting enzyme 2 (ACE2) - is there any scientific evidence for controversy? J Intern Med. 2020 Oct;288(4):410-21. ]. Unless there exist evidence-based indication and robust data to discontinue these important life-saving medications.

Functionally, there are two forms of ACE2, the full-length ACE2 that contains a structural transmembrane domain, which anchors its extracellular domain to the plasma membrane and soluble Angiotensin Converting Enzyme 2 (sACE2) that lacks the membrane anchor and circulates in small amounts in the blood [116116. Wysocki J, Ye M, Rodriguez E, González-Pacheco FR, Barrios C, Evora K, Schuster M, Loibner H, Brosnihan KB, Ferrario CM, Penninger JM, Batlle D. Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension. Hypertension. 2010 Jan;55(1):90-8. ], other RAAS-related therapy which has been approached for COVID-19 treatment. Increasing ACE2 activity in systemic, not tissue, by human recombinant sACE2 administration may provide a new therapeutic target in states of Ang II-dependent hypertension by enhancing Ang II degradation and increasing Ang 1-7 levels [116116. Wysocki J, Ye M, Rodriguez E, González-Pacheco FR, Barrios C, Evora K, Schuster M, Loibner H, Brosnihan KB, Ferrario CM, Penninger JM, Batlle D. Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension. Hypertension. 2010 Jan;55(1):90-8. ].

In vitro study showed that SARS-CoV replication was blocked by a soluble form of ACE2 in monkey kidney cell line, Vero-E6 [5959. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003 Nov 27;426(6965):450-4. ]. SARS-CoV-2 have limited potential to escape sACE2-mediated neutralization, since its binding with the virus blocks S protein and prevents its interaction with full length ACE2. Consequently, coronavirus attachment and internalization in the host cells is impaired [108108. Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? Clin Sci (Lond). 2020 Mar 13;134(5):543-5. ], an outcome that attenuates virulence [117117. Chan KK, Dorosky D, Sharma P, Abbasi SA, Dye JM, Kranz DM, Herbert AS, Procko E. Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2. Science. 2020 Sep 4;369(6508):1261-5. ].

Based on these findings, Batlle et al. [108108. Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? Clin Sci (Lond). 2020 Mar 13;134(5):543-5. ] proposed that sACE2 may act as a competitive interceptor of SARS-CoV-2 and other coronaviruses by preventing binding of the viral particle to the surface-bound, full-length ACE2. They suggest that the use of sACE2 as a potential approach for coronavirus infection therapy should be urgently tested [108108. Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? Clin Sci (Lond). 2020 Mar 13;134(5):543-5. ].

As already described, ACE2 enzymatic functions protect against organ injury by cleavage and disposal of Ang II and the formation of Ang 1-7, as well as cleaving DABK, which is a proinflammatory peptide. In line, there are pharmacokinetic studies regarding human recombinant sACE2 in healthy volunteers and clinical trials have been developed as treatment for acute respiratory distress syndrome [118118. Haschke M, Schuster M, Poglitsch M, Loibner H, Salzberg M, Bruggisser M, Penninger J, Krähenbühl S. Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. Clin Pharmacokinet. 2013 Sep;52(9):783-92. -120120. Hemnes AR, Rathinasabapathy A, Austin EA, Brittain EL, Carrier EJ, Chen X, Fessel JP, Fike CD, Fong P, Fortune N, Gerszten RE, Johnson JA, Kaplowitz M, Newman JH, Piana R, Pugh ME, Rice TW, Robbins IM, Wheeler L, Yu C, Loyd JE, West J. A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. Eur Respir J. 2018 Jun 21;51(6):1702638. ]. Very recent cell-based assays using engineering human sACE2 have been developed to optimize its binding to SARS-CoV-2 [117117. Chan KK, Dorosky D, Sharma P, Abbasi SA, Dye JM, Kranz DM, Herbert AS, Procko E. Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2. Science. 2020 Sep 4;369(6508):1261-5. ]. Using human organoids models, Monteil et al. [121121. Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, Leopoldi A, Garreta E, Hurtado Del Pozo C, Prosper F, Romero JP, Wirnsberger G, Zhang H, Slutsky AS, Conder R, Montserrat N, Mirazimi A, Penninger JM. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020 May 14;181(4):905-913.e7. ] demonstrated that SARS-CoV-2 can directly infect human blood vessel and kidney organoids, and human sACE2 can inhibit these viral infections [121121. Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, Leopoldi A, Garreta E, Hurtado Del Pozo C, Prosper F, Romero JP, Wirnsberger G, Zhang H, Slutsky AS, Conder R, Montserrat N, Mirazimi A, Penninger JM. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020 May 14;181(4):905-913.e7. ]. There are no studies in vivo ensuring efficacy of sACE2 human therapy yet. Furthermore, it is worth mentioning that there is a concern that blood pressure could fall excessively due to systemic inactivation of Ang II by sACE2 administration. On the other hand, increased levels of intrinsic sACE2 in COVID-19 patients can represent an additional risk, as the ACE2 anchored in cell membrane would lacks its N-domain after shedding, thus ACE2 local effects mediated by its catalytic action may decrease.

In late phases of COVID-19 development, when antiviral treatments are not so effective and ACE2 is markedly downregulated, the administration of ACE2 activator agents becomes a daring therapeutic proposal. Diminazene aceturate is an old antiparasitic that has been substantially studied due to its ACE2 activators properties, which restore protective RAAS and KKS axes [122122. da Silva Oliveira GL, de Freitas RM. Diminazene aceturate--an antiparasitic drug of antiquity: advances in pharmacology & therapeutics. Pharmacol Res. 2015 Dec;102:138-57. ].

As this compound has anti-inflammatory and tissue protectant profile, in addition to be an FDA-approved drug [122122. da Silva Oliveira GL, de Freitas RM. Diminazene aceturate--an antiparasitic drug of antiquity: advances in pharmacology & therapeutics. Pharmacol Res. 2015 Dec;102:138-57. ,123123. Rajapaksha IG, Mak KY, Huang P, Burrell LM, Angus PW, Herath CB. The small molecule drug diminazene aceturate inhibits liver injury and biliary fibrosis in mice. Sci Rep. 2018 Jul 5;8(1):10175. ], Nicolau et al. [124124. Nicolau LAD, Nolêto IRSG, Medeiros JVR. Could a specific ACE2 activator drug improve the clinical outcome of SARS-CoV-2? A potential pharmacological insight. Expert Rev Clin Pharmacol. 2020 Aug;13(8):807-11. ] hypothesized the use of diminazene aceturate as potential therapeutic strategy for late stage mainly in pulmonary complications provoked by SARS-CoV-2 infection. It could improve clinical outcomes by reduction of proinflammatory cytokines and augmenting surfactant proteins ACE2-dependent, consequent effects of ACE2 activation [124124. Nicolau LAD, Nolêto IRSG, Medeiros JVR. Could a specific ACE2 activator drug improve the clinical outcome of SARS-CoV-2? A potential pharmacological insight. Expert Rev Clin Pharmacol. 2020 Aug;13(8):807-11. ].

Taken together, the protective effects of RAAS blockers on the heart and blood vessels are at least partly mediated by the direct or indirect KKS activation, and reduction of Ang II/AT1R signaling, due to decreased Ang II production or AT1R blockade, increase of Ang l levels and consequently augmented Ang 1-7 by the action of Neprilisin. Or in the case of sACE2 therapy and ACE2 activators, there is a counterbalancing of the deleterious effects caused by downregulation of ACE2 in SARS-CoV-2 infection, as shown in Figure 2. In this way, it occurs a direct increased formation of protective angiotensin, Ang 1-7 from Ang II and Ang 1-9 from Ang I, in addition to reducing DABK levels and its inflammatory outcomes.

Figure 2
Schematic of COVID-19 outcomes on the renin-angiotensin-aldosterone and kallikrein-kinin systems, and proposed therapies with RAAS blockers, B1R and recombinant sACE2. (I) SARS-CoV-2/ACE2 complex is internalized by endocytosis, (II) triggering viral replication and reduction of transmembrane ACE2, which provokes (IIIa) the imbalance of RAAS and KKS, with (IIIb) Ang II/AT1R and DABK/B1R pathway activation, respectively. (IVa) Ang II/AT1R upregulation induces ADAM-17 activation, which is responsible for (V) ACE2 shedding that can contribute to depletion of ACE2 local effects, in addition (IVb) Ang II/AT1R promotes inflammatory and fibrotic processes. (IVc) DABK/B1R upregulation also triggers pro-inflammatory cascades. It is pointed out the actions of RAAS blockers (ACEI and ARB), ACE2 activators and B1R antagonists, counterbalancing the deleterious effects of downregulation of ACE2 in SARS-CoV-2 infection. In detail, (VI) the effect of sACE2 recombinant as therapy, that act as a competitive interceptor of SARS-CoV-2 by preventing binding of coronavirus to the surface-bound, besides providing increased Ang 1-7 circulating levels. ACEI: angiotensin-converting enzyme inhibitors; ACE2: angiotensin-converting enzyme 2; ADAM-17: A-disintegrin and metalloproteinase 17; Ang 1-7: angiotensin 1-7; Ang II: angiotensin II; AT1R: angiotensin II receptor type 1; ARB: angiotensin II receptor blockers; BK: bradykinin; B1R: kinin B1 receptor; B2R: kinin B2 receptor; DABK, des-Arg9 bradykinin; KKS: kallikrein-kinin system; RAAS: renin-angiotensin-aldosterone system; sACE2: soluble angiotensin converting enzyme 2.

Potential therapeutic strategies related with the RAAS components also comprise the prevention of S protein SARS-CoV-2/ACE2 interaction by viral receptor-binding domain blockade. Which may include the use of ACE2-derived peptides, small molecule inhibitors, ACE2 antibody or single chain antibody fragment against ACE2[9292. Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, Raizada MK, Grant MB, Oudit GY. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res. 2020 May 8;126(10):1456-74. ].

The enhancement of DABK/B1R signaling, caused by reduced ACE2 levels after coronavirus infection, triggers consequential events as fluid extravasation, leukocyte recruitment to the lung and may increase the risk of capillary permeability, acute respiratory distress syndrome and multiple organ failure [4141. Sodhi CP, Wohlford-Lenane C, Yamaguchi Y, Prindle T, Fulton WB, Wang S, McCray Jr PB, Chappell M, Hackam DJ, Jia H. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J Physiol Lung Cell Mol Physiol. 2018 Jan 1;314(1):L17-31. ]. Administration of B1R antagonists in experimental models of sepsis shown prevented hemodynamic derangement and attenuates the risk of multi-organ failure [125125. Murugesan P, Jung B, Lee D, Khang G, Doods H, Wu D. Kinin B1 receptor inhibition with BI113823 reduces inflammatory response, mitigates organ injury, and improves survival among rats with severe sepsis. J Infect Dis. 2016 Feb 15;213(4):532-40. ].

Regarding COVID-19 patients that present pulmonary edema early in disease, this condition added to enhancement of local immune cell influx and proinflammatory cytokines leading to damage, has been resulting in a very high number of intensive care unit admissions. It was hypothesized that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disorders caused by COVID-19 and might prevent acute respiratory distress syndrome [9999. van de Veerdonk FL, Netea MG, van Deuren M, van der Meer JW, de Mast Q, Brüggemann RJ, van der Hoeven H. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife. 2020 Apr 27;9:e57555. ,100100. van de Veerdonk F, Netea MG, van Deuren M, van der Meer JWM, de Mast Q, Bruggemann RJ,van der Hoeven H. Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach. Preprints. 2020 Apr 3[cited 2020 Oct 4]. Available from: Available from: https://www.preprints.org/manuscript/202004.0023/v1 .
https://www.preprints.org/manuscript/202...
], besides being able to collaborate with indirectly response to anti-inflammatory agents. Thus, there are indications that the KKS receptors antagonists can also be an option for symptoms COVID-19 treatment.

Conclusion

SARS-CoV-2 infection is intrinsically related to the RAAS, as the viral internalization apparatus is driven by ACE2, and indirectly linked to the KKS, due to the action of this enzyme on the degradation of DABK. Imbalance in the RAAS and KKS (caused primarily by loss of ACE2 activity in patients with COVID-19 are contributing factors to consequent deregulation of blood pressure), loss of protective effects, organ damage and exacerbated tissue and systemic inflammation, among others, are key factors that may explain the severity of the disease. These conditions make it tricky for the organism to react against the pathogenesis considering that, per se, it weakens the health conditions of patients.

Even with the proven increased ACE2 levels in continuous treatment with RAAS blockers, in view of its protective role, scientific communities strongly suggest a rationale for continuing this therapy in patients with COVID-19 infection. In addition, since it is responsible for metabolizing Ang II into Ang 1-7, a dominant mechanism for negative regulation on the RAAS, and for inactivating DABK, an inductor of pro-inflammatory repercussions of the KKS, ACE2 has relevant properties that have to be further explored as tools for the treatment of COVID-19 patients. Taken together, there are gaps in knowledge that highlight the need for new studies to design more effective therapeutic and prophylactic strategies.

Abbreviations

ACE: angiotensin I-converting enzyme; ACEI: ACE inhibitor; ADAM-17: A-disintegrin and metalloproteinase 17; Ang 1-5: angiotensin 1-5; Ang 1-7: angiotensin 1-7; Ang 1-9: angiotensin 1-9; Ang I: angiotensin I; Ang II: angiotensin II; ARB: angiotensin II receptor blocker; AT1R: angiotensin II receptor type 1; AT2R: angiotensin II receptor type 2; B1R: kinin B1 receptor; B2R: kinin B2 receptor; BK: bradykinin; BPF: bradykinin potentiating factor; COVID-19: coronavirus disease 2019; DABK: des-Arg9bradykinin; eNOS: endothelial nitric oxide synthase; HMWK: high molecular weight kininogen; iNOS: inducible nitric oxide synthase; KKS: kallikrein-kinin system; LMWK: low molecular weight kininogen; Lys-BK: lysine-bradykinin; MERS: Middle East respiratory syndrome; PGE2: prostaglandin E2; RAAS: renin-angiotensin-aldosterone system; S protein: spike protein; sACE2: soluble angiotensin converting enzyme 2; SARS: severe acute respiratory syndrome; TACE: TNF-(-converting enzyme; TNF-(: tumor necrosis factor-(.

Acknowledgments

We are most grateful to the staff of JVATiTD and the guest editors of the thematic series “Inflammation: from bench to bedside” for their invitation to contribute to the journal. We would like to thank the JBS “Fazer o Bem Faz Bem” Program, Fundação de Apoio à Universidade Federal de São Paulo (Fap-UNIFESP proc. no. 1424) and the Oswaldo Ramos Foundation/Hospital do Rim for their support of this research. We also would like to give special thanks to the Brazilian funding agencies São Paulo Research Foundation (FAPESP - proc no. 2017/17027-0, 2018/16653-7 and 2018/23953-7), Coordination for the Improvement of Higher Education Personnel (CAPES) and National Council for Scientific and Technological Development (CNPq).

References

  • 1. Chan JFW, Yuan S, Kok KH, To KKW, Chu H, Yang J, Xing F, Liu J, Yip CCY, Poon RW, Tsoi HW, Lo SKF, Chan KH, Poon VKM, Chan WM, Ip JD, Cai JP, Cheng VCC, Chen H, Hui CK, Yuen KY. A familial cluster of pneumonia associated with the 2019 novel Coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet . 2020 Feb 15;395(10223):514-23.
  • 2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506.
  • 3. Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet. 2020 Feb 15;395(10223):470-3.
  • 4. World Health Organization (WHO) [Internet]. Geneva: WHO; -2021. WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020 [cited 2020 Jul 14]. Available from: Available from: https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020
    » https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020
  • 5. World Health Organization (WHO) [Internet]. Geneva: WHO ; -2021. Dashboard. [cited 2021 Nov 04]. Available from: Available from: https://covid19.who.int
    » https://covid19.who.int
  • 6. Sher L. The impact of the COVID-19 pandemic on suicide rates. QJM. 2020 Oct 1;113(10):707-12.
  • 7. Nicola M, Alsafi Z, Sohrabi C, Kerwan A, Al-Jabir A, Iosifidis C, Agha M, Agha R. The socio-economic implications of the coronavirus pandemic (COVID-19): a review. Int J Surg. 2020 Jun;78:185-93.
  • 8. Kastner M, Tricco AC, Soobiah C, Lillie E, Perrier L, Horsley T, Welch V, Cogo E, Antony J, Straus SE. What is the most appropriate knowledge synthesis method to conduct a review? Protocol for a scoping review. BMC Med Res Methodol. 2012 Aug 3;12:114.
  • 9. Tricco AC, Lillie E, Zarin W, O’Brien KK, Colquhoun H, Levac D, Moher D, Peters MDJ, Horsley T, Weeks L, Hempel S, Akl EA, Chang C, McGowan J, Stewart L, Hartling L, Aldcroft A, Wilson MG, Garritty C, Lewin S, Godfrey CM, Macdonald MT, Langlois EV, Soares-Weiser K, Moriarty J, Clifford T, Tunçalp Ö, Straus SE. PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Ann Intern Med. 2018 Oct 2;169(7):467-73.
  • 10. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000 Sep 1;87(5):E1-9.
  • 11. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000 Oct 27;275(43):33238-43.
  • 12. McKinney CA, Fattah C, Loughrey CM, Milligan G, Nicklin SA. Angiotensin-(1-7) and angiotensin-(1-9): function in cardiac and vascular remodelling. Clin Sci (Lond). 2014 Jun;126(12):815-27.
  • 13. Marshall RP, Gohlke P, Chambers RC, Howell DC, Bottoms SE, Unger T, McAnulty RJ, Laurent GJ. Angiotensin II and the fibroproliferative response to acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2004 Jan;286(1):L156-164.
  • 14. Soro-Paavonen A, Gordin D, Forsblom C, Rosengard-Barlund M, Waden J, Thorn L, Sandholm N, Thomas MC, Groop PH, FinnDiane Study Group. Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications. J Hypertens. 2012 Feb;30(2):375-83.
  • 15. Zhang X, Zheng J, Yan Y, Ruan Z, Su Y, Wang J, Huang H, Zhang Y, Wang W, Gao J, Chi Y, Lu X, Liu Z. Angiotensin-converting enzyme 2 regulates autophagy in acute lung injury through AMPK/mTOR signaling. Arch Biochem Biophys. 2019 Sep 15;672:108061.
  • 16. Santos RAS, Simoes e Silva AC, Maric C, Silva DMR, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SVB, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8258-63.
  • 17. Santos RA. Angiotensin-(1-7). Hypertension. 2014 Jun;63(6):1138-47.
  • 18. Meng Y, Li T, Zhou GS, Chen Y, Yu CH, Pang MX, Li W, Li Y, Zhang WY, Li X. The angiotensin-converting enzyme 2/angiotensin (1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rho kinase pathway. Antioxid Redox Signal. 2015 Jan 20;22(3):241-58.
  • 19. Wang W, Bodiga S, Das SK, Lo J, Patel V, Oudit GY. Role of ACE2 in diastolic and systolic heart failure. Heart Fail Rev. 2012 Sep;17(4-5):683-91.
  • 20. Jia H. Pulmonary angiotensin-converting enzyme 2 (ACE2) and inflammatory lung disease. Shock. 2016 Sep;46(3):239-48.
  • 21. Flores-Muñoz M, Godinho BMDC, Almalik A, Nicklin SA. Adenoviral delivery of angiotensin-(1-7) or angiotensin-(1-9) inhibits cardiomyocyte hypertrophy via the mas or angiotensin type 2 receptor. PloS One. 2012;7(9):e45564.
  • 22. Flores-Munoz M, Work LM, Douglas K, Denby L, Dominiczak AF, Graham D, Nicklin SA. Angiotensin-(1-9) attenuates cardiac fibrosis in the stroke-prone spontaneously hypertensive rat via the angiotensin type 2 receptor. Hypertension. 2012 Feb;59(2):300-7.
  • 23. Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, Godbout K, Parsons T, Baronas E, Hsieh F, Acton S, Patane M, Nichols A, Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002 Apr 26;277(17):14838-43.
  • 24. Donoghue M, Wakimoto H, Maguire CT, Acton S, Hales P, Stagliano N, Fairchild-Huntress V, Xu J, Lorenz JN, Kadambi V, Berul CI, Breitbart RE. Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins. J Mol Cell Cardiol. 2003 Sep;35(9):1043-53.
  • 25. Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ Res. 2016 Apr 15;118(8):1313-26.
  • 26. Qi Y, Kim S, Richards EM, Raizada MK, Pepine CJ. Gut microbiota: potential for a unifying hypothesis for prevention and treatment of hypertension. Circ Res. 2017 May 26;120(11):1724-6.
  • 27. de Oliveira AP, Lopes ALF, Pacheco G, de Sá Guimarães Nolêto IR, Nicolau LAD, Medeiros JVR. Premises among SARS-CoV-2, dysbiosis and diarrhea: walking through the ACE2/mTOR/autophagy route. Med Hypotheses. 2020 Nov;144:110243.
  • 28. Revenko AS, Gao D, Crosby JR, Bhattacharjee G, Zhao C, May C, Gailani D, Monia BP, MacLeod AR. Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. Blood. 2011 Nov 10;118(19):5302-11.
  • 29. Renné T, Schmaier AH, Nickel KF, Blombäck M, Maas C. In vivo roles of factor XII. Blood. 2012 Nov 22;120(22):4296-303.
  • 30. Rocha e Silva M, Beraldo WT, Rosenfeld G. Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin. Am J Physiol. 1949 Feb;156(2):261-73.
  • 31. Ferreira SH, Rocha e Silva M. Potentiation of bradykinin and eledoisin by BPF (bradykinin potentiating factor) from Bothrops jararaca venom. Experientia. 1965 Jun 15;21(6):347-9.
  • 32. Ferreira SH, Vane JR. The disappearance of bradykinin and eledoisin in the circulation and vascular beds of the cat. Br J Pharmacol Chemother. 1967 Jun;30(2):417-24.
  • 33. Ferreira SH. A bradykinin-potentiating factor (bpf) present in the venom of Bothrops jararca Br J Pharmacol Chemother. 1965 Feb;24(1):163-9.
  • 34. Downey P. Profile of Sérgio Ferreira. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19035-7.
  • 35. Golias C, Charalabopoulos A, Stagikas D, Charalabopoulos K, Batistatou A. The kinin system--bradykinin: biological effects and clinical implications. Multiple role of the kinin system--bradykinin. Hippokratia. 2007 Jul;11(3):124-8.
  • 36. Bossi F, Peerschke EI, Ghebrehiwet B, Tedesco F. Cross-talk between the complement and the kinin system in vascular permeability. Immunol Lett. 2011 Oct 30;140(1-2):7-13.
  • 37. Mossberg M, Ståhl AL, Kahn R, Kristoffersson AC, Tati R, Heijl C, Segelmark M, Leeb-Lundberg LMF, Karpman D. C1-inhibitor decreases the release of vasculitis-like chemotactic endothelial microvesicles. J Am Soc Nephrol. 2017 Aug;28(8):2472-81.
  • 38. Yang HY, Erdös EG, Levin Y. A dipeptidyl carboxypeptidase that converts angiotensin I and inactivates bradykinin. Biochim Biophys Acta. 1970 Aug 21;214(2):374-6.
  • 39. Murphey LJ, Malave HA, Petro J, Biaggioni I, Byrne DW, Vaughan DE, Luther JM, Pretorius M, Brown NJ. Bradykinin and its metabolite bradykinin 1-5 inhibit thrombin-induced platelet aggregation in humans. J Pharmacol Exp Ther. 2006 Sep;318(3):1287-92.
  • 40. Hasan AA, Amenta S, Schmaier AH. Bradykinin and its metabolite, Arg-Pro-Pro-Gly-Phe, are selective inhibitors of alpha-thrombin-induced platelet activation. Circulation. 1996 Aug 1;94(3):517-28.
  • 41. Sodhi CP, Wohlford-Lenane C, Yamaguchi Y, Prindle T, Fulton WB, Wang S, McCray Jr PB, Chappell M, Hackam DJ, Jia H. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J Physiol Lung Cell Mol Physiol. 2018 Jan 1;314(1):L17-31.
  • 42. Pitarresi TM, Rubattu S, Heinrikson R, Sealey JE. Reversible cryoactivation of recombinant human prorenin. J Biol Chem. 1992 Jun 15;267(17):11753-9.
  • 43. Suzuki F, Hayakawa M, Nakagawa T, Nasir UM, Ebihara A, Iwasawa A, Ishida Y, Nakamura Y, Murakami K. Human prorenin has “gate and handle” regions for its non-proteolytic activation. J Biol Chem. 2003 Jun 20;278(25):22217-22.
  • 44. Kikkawa Y, Yamanaka N, Tada J, Kanamori N, Tsumura K, Hosoi K. Prorenin processing and restricted endoproteolysis by mouse tissue kallikrein family enzymes (mK1, mK9, mK13, and mK22). Biochim Biophys Acta. 1998 Jan 15;1382(1):55-64.
  • 45. Hsueh WA, Baxter JD. Human prorenin. Hypertens. 1991 Apr;17(4):469-77.
  • 46. Sealey JE, Atlas SA, Laragh JH, Oza NB, Ryan JW. Human urinary kallikrein converts inactive to active renin and is a possible physiological activator of renin. Nature. 1978 Set 14;275(5676):144-5.
  • 47. Derkx FH, Tan-Tjiong HL, Man in ’t Veld AJ, Schalekamp MP, Schalekamp MA. Activation of inactive plasma renin by plasma and tissue kallikreins. Clin Sci (Lond). 1979 Oct;57(4):351-7.
  • 48. Leckie BJ, Morton JJ. Relation between renin and prorenin in plasma from hypertensive patients and normal people: evidence for different renin:prorenin ratios. J Hum Hypertens. 1995 Jun;9(6):493-6.
  • 49. Zhang W, Jernerén F, Lehne BC, Chen MH, Luben RN, Johnston C, Elshorbagy A, Eppinga RN, Scott WR, Adeyeye E, Scott J, Böger RH, Khaw KT, van der Harst P, Wareham NJ, Vasan RS, Chambers JC, Refsum H, Kooner JS. Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels. Thromb Haemost. 2016 Nov 30;116(6):1041-9.
  • 50. Biswas N, Maihofer AX, Mir SA, Rao F, Zhang K, Khandrika S, Mahata M, Friese RS, Hightower CM, Mahata SK, Baker DG, Nievergelt CM, Vaingankar SM, O'Connor DT. Polymorphisms at the F12 and KLKB1 loci have significant trait association with activation of the renin-angiotensin system. BMC Med Genet. 2016 Mar 11;17:21.
  • 51. Lieb W, Chen MH, Teumer A, de Boer RA, Lin H, Fox ER, Musani SK, Wilson JG, Wang TJ, Völzke H, Petersen AK, Meisinger C, Nauck M, Schlesinger S, Li Y, Menard J, Hercberg S, Wichmann HE, Völker U, Rawal R, Bidlingmaier M, Hannemann A, Dörr M, Rettig R, van Gilst WH, van Veldhuisen DJ, Bakker SJ, Navis G, Wallaschofski H, Meneton P, van der Harst P, Reincke M, Vasan RS, CKDGen Consortium, ICBP, EchoGen Consortium. Genome-wide meta-analyses of plasma renin activity and concentration reveal association with the kininogen 1 and prekallikrein genes. Circ Cardiovasc Genet. 2015 Feb;8(1):131-40.
  • 52. Lara LS, Bourgeois CRT, El-Dahr SS, Prieto MC. Bradykinin/B2 receptor activation regulates renin in M-1 cells via protein kinase C and nitric oxide. Physiol Rep. 2017 Apr;5(7):e13211.
  • 53. Schweda F, Klar J, Narumiya S, Nüsing RM, Kurtz A. Stimulation of renin release by prostaglandin E2 is mediated by EP2 and EP4 receptors in mouse kidneys. Am J Physiol Renal Physiol. 2004 Sep;287(3):F427-33.
  • 54. Deddish PA, Marcic B, Jackman HL, Wang HZ, Skidgel RA, Erdös EG. N-domain-specific substrate and C-domain inhibitors of angiotensin-converting enzyme: angiotensin-(1-7) and keto-ACE. Hypertension. 1998 Apr;31(4):912-7.
  • 55. Tschöpe C, Schultheiss HP, Walther T. Multiple interactions between the renin-angiotensin and the kallikrein-kinin systems: role of ACE inhibition and AT1 receptor blockade. J Cardiovasc Pharmacol. 2002 Apr;39(4):478-87.
  • 56. Schmaier AH. The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. J Thromb Haemost. 2016 Jan;14(1):28-39.
  • 57. Parekh RU, Robidoux J, Sriramula S. Kinin B1 Receptor blockade prevents angiotensin ii-induced neuroinflammation and oxidative stress in primary hypothalamic neurons. Cell Mol Neurobiol. 2020 Jul;40(5):845-57.
  • 58. Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, Miyazaki M, Nozawa Y, Ozono R, Nakagawa K, Miwa T, Kawada N, Mori Y, Shibasaki Y, Tanaka Y, Fujiyama S, Koyama Y, Fujiyama A, Takahashi H, Iwasaka T. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest. 1999 Oct;104(7):925-35.
  • 59. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003 Nov 27;426(6965):450-4.
  • 60. Turner AJ, Hiscox JA, Hooper NM. ACE2: from vasopeptidase to SARS virus receptor. Trends Pharmacol Sci. 2004 Jun;25(6):291-4.
  • 61. Clarke NE, Turner AJ. Angiotensin-converting enzyme 2: the first decade. Int J Hypertens. 2012;2012:307315.
  • 62. Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M, Sigl V, Hanada T, Hanada R, Lipinski S, Wild B, Camargo SMR, Singer D, Richter A, Kuba K, Fukamizu A, Schreiber S, Clevers H, Verrey F, Rosenstiel P, Penninger JM. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 2012 Jul 15;487(7408):477-81.
  • 63. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 27;367(6485):1444-8.
  • 64. Lopera Maya EA, van der Graaf A, Lanting P, van der Geest M, Fu J, Swertz M, Franke L, Wijmenga C, Deelen P, Zhernakova A, Sanna S; Lifelines Cohort Study. Lack of association between genetic variants at ACE2 and TMPRSS2 genes involved in SARS-CoV-2 infection and human quantitative phenotypes. Front Genet. 2020 Jun 8;11:613.
  • 65. Moitinho MS, Belasco AGS, Barbosa DA, Fonseca CD. Acute kidney injury by SARS-CoV-2 virus in patients with COVID-19: an integrative review. Rev Bras Enferm. 2020;73 Suppl 2:e20200354.
  • 66. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020 May;17(5):259-60.
  • 67. Manjili RH, Zarei M, Habibi M, Manjili MH. COVID-19 as an acute inflammatory disease. J Immunol. 2020 Jul 1;205(1):12-9.
  • 68. Vaninov N. In the eye of the COVID-19 cytokine storm. Nat Rev Immunol. 2020 May;20(5):277.
  • 69. Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017 Jul;39:517-28.
  • 70. García LF. Immune response, inflammation, and the clinical spectrum of COVID-19. Front Immunol. 2020 Jun 16;11:1441.
  • 71. Ortega JT, Serrano ML, Pujol FH, Rangel HR. Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: an in silico analysis. EXCLI J. 2020 Mar 18;19:410-7.
  • 72. Carsana L, Sonzogni A, Nasr A, Rossi RS, Pellegrinelli A, Zerbi P, Rech R, Colombo R, Antinori S, Corbellino M, Galli M, Catena E, Tosoni A, Gianatti A, Nebuloni M. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study. Lancet Infect Dis. 2020 Oct;20(10):1135-40.
  • 73. Zhou L, Xu Z, Castiglione GM, Soiberman US, Eberhart CG, Duh EJ. ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection. Ocul Surf. 2020 Oct;18(4):537-44.
  • 74. Aragão DS, Cunha TS, Arita DY, Andrade MCC, Fernandes AB, Watanabe IKM, Mortara RA, Casarini DE. Purification and characterization of angiotensin converting enzyme 2 (ACE2) from murine model of mesangial cell in culture. Int J Biol Macromol. 2011 Jul 1;49(1):79-84.
  • 75. Spak E, Hallersund P, Edebo A, Casselbrant A, Fändriks L. The human duodenal mucosa harbors all components for a local renin angiotensin system. Clin Sci (Lond). 2019 Apr 29;133(8):971-82.
  • 76. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Apr;8(4):e21.
  • 77. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 May;8(5):475-81.
  • 78. Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM, Liu XQ, Chen RC, Tang CL, Wang T, Ou CQ, Li L, Chen PY, Sang L, Wang W, Li JF, Li CC, Ou LM, Cheng B, Xiong S, Ni ZY, Xiang J, Hu Y, Liu L, Shan H, Lei CL, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Cheng LL, Ye F, Li SY, Zheng JP, Zhang NF, Zhong NS, He JX, China Medical Treatment Expert Group for COVID-19. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. Eur Respir J. 2020 May 14;55(5):2000547.
  • 79. Ni G, Ma Z, Damania B. cGAS and STING: at the intersection of DNA and RNA virus-sensing networks. PLoS Pathog. 2018 Aug 16;14(8):e1007148.
  • 80. Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM, Butany J. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest. 2009 Jul;39(7):618-25.
  • 81. Glowacka I, Bertram S, Herzog P, Pfefferle S, Steffen I, Muench MO, Simmons G, Hofmann H, Kuri T, Weber F, Eichler J, Drosten C, Pöhlmann S. Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63. J Virol. 2010 Jan;84(2):1198-205.
  • 82. Haga S, Nagata N, Okamura T, Yamamoto N, Sata T, Yamamoto N, Sasazuki T, Ishizaka Y. TACE antagonists blocking ACE2 shedding caused by the spike protein of SARS-CoV are candidate antiviral compounds. Antiviral Res. 2010 Mar;85(3):551-5.
  • 83. Samavati L, Uhal BD. ACE2, much more than just a receptor for SARS-COV-2 Front Cell Infect Microbiol. 2020 Jun 5;10:317.
  • 84. Xie J, Tong Z, Guan X, Du B, Qiu H. Clinical characteristics of patients who died of coronavirus disease 2019 in China. JAMA Netw Open. 2020 Apr 1;3(4):e205619.
  • 85. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS, China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-20.
  • 86. Sharma G, Volgman AS, Michos ED. Sex differences in mortality from COVID-19 pandemic: are men vulnerable and women protected? JACC Case Rep. 2020 Jul 15;2(9):1407-10.
  • 87. Bhatia K, Zimmerman MA, Sullivan JC. Sex differences in angiotensin-converting enzyme modulation of Ang (1-7) levels in normotensive WKY rats. Am J Hypertens. 2013 May;26(5):591-8.
  • 88. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2 Cardiovasc Res. 2020 May 1;116(6):1097-100.
  • 89. Lambert DW, Yarski M, Warner FJ, Thornhill P, Parkin ET, Smith AI, Hooper NM, Turner AJ. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem. 2005 Aug 26;280(34):30113-9.
  • 90. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature. 1997 Feb 20;385(6618):729-33.
  • 91. Gooz M. ADAM-17: the enzyme that does it all. Crit Rev Biochem Mol Biol. 2010 Apr;45(2):146-69.
  • 92. Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, Raizada MK, Grant MB, Oudit GY. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res. 2020 May 8;126(10):1456-74.
  • 93. Patel VB, Clarke N, Wang Z, Fan D, Parajuli N, Basu R, Putko B, Kassiri Z, Turner AJ, Oudit GY. Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive feedback mechanism in the RAS. J Mol Cell Cardiol. 2014 Jan;66:167-76.
  • 94. Xu J, Sriramula S, Xia H, Moreno-Walton L, Culicchia F, Domenig O, Poglitsch M, Lazartigues E. Clinical relevance and role of neuronal AT1 receptors in ADAM17-mediated ACE2 shedding in neurogenic hypertension. Circ Res. 2017 Jun 23;121(1):43-55.
  • 95. Nicolau LAD, Magalhães PJC, Vale ML. What would Sérgio Ferreira say to your physician in this war against COVID-19: how about kallikrein/kinin system? Med Hypotheses. 2020 Oct;143:109886.
  • 96. Kuhr F, Lowry J, Zhang Y, Brovkovych V, Skidgel RA. Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors. Neuropeptides. 2010 Apr;44(2):145-54.
  • 97. Tsai YJ, Hao SP, Chen CL, Lin BJ, Wu WB. Involvement of B2 receptor in bradykinin-induced proliferation and proinflammatory effects in human nasal mucosa-derived fibroblasts isolated from chronic rhinosinusitis patients. PloS One. 2015 May 13;10(5):e0126853.
  • 98. Ferreira SH, Lorenzetti BB, Poole S. Bradykinin initiates cytokine-mediated inflammatory hyperalgesia. Br J Pharmacol. 1993 Nov;110(3):1227-31.
  • 99. van de Veerdonk FL, Netea MG, van Deuren M, van der Meer JW, de Mast Q, Brüggemann RJ, van der Hoeven H. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife. 2020 Apr 27;9:e57555.
  • 100. van de Veerdonk F, Netea MG, van Deuren M, van der Meer JWM, de Mast Q, Bruggemann RJ,van der Hoeven H. Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach. Preprints. 2020 Apr 3[cited 2020 Oct 4]. Available from: Available from: https://www.preprints.org/manuscript/202004.0023/v1
    » https://www.preprints.org/manuscript/202004.0023/v1
  • 101. Oehmcke-Hecht S, Köhler J. Interaction of the human contact system with pathogens-an update. Front Immunol. 2018 Feb 26;9:312.
  • 102. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers D, Kant KM, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res. 2020 Jul;191:148-50.
  • 103. Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, Diz DI, Gallagher PE. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005 May 24;111(20):2605-10.
  • 104. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS Coronavirus. J Virol. 2020 Mar 17;94(7):e00127-20.
  • 105. Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res. 2017 Nov;125(Pt A):21-38.
  • 106. Erdös EG, Marcic BM. Kinins, receptors, kininases and inhibitors--where did they lead us? Biol Chem. 2001 Jan;382(1):43-7.
  • 107. Ignjatovic T, Tan F, Brovkovych V, Skidgel RA, Erdös EG. Novel mode of action of angiotensin I converting enzyme inhibitors: direct activation of bradykinin B1 receptor. J Biol Chem. 2002 May 10;277(19):16847-52.
  • 108. Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? Clin Sci (Lond). 2020 Mar 13;134(5):543-5.
  • 109. Santesmasses D, Castro JP, Zenin AA, Shindyapina AV, Gerashchenko MV, Zhang B, Kerepesi C, Yim SH, Fedichev PO, Gladyshev VN. COVID-19 is an emergent disease of aging. Aging Cell. 2020 Oct;19(10):e13230.
  • 110. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-62.
  • 111. Sparks MA, South A, Welling P, Luther JM, Cohen J, Byrd JB, Burrell LM, Batlle D, Tomlinson L, Bhalla V, Rheault MN, Soler MJ, Swaminathan S, Hiremath S. Sound science before quick judgement regarding RAS blockade in COVID-19. Clin J Am Soc Nephrol. 2020 May 7;15(5):714-6.
  • 112. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005 Aug;11(8):875-9.
  • 113. Yang P, Gu H, Zhao Z, Wang W, Cao B, Lai C, Yang X, Zhang L, Duan Y, Zhang S, Chen W, Zhen W, Cai M, Penninger JM, Jiang C, Wang X. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep. 2014 Nov 13;4:7027.
  • 114. Zhang P, Zhu L, Cai J, Lei F, Qin JJ, Xie J, Liu YM, Zhao YC, Huang X, Lin L, Xia M, Chen MM, Cheng X, Zhang X, Guo D, Peng Y, Ji YX, Chen J, She ZG, Wang Y, Xu Q, Tan R, Wang H, Lin J, Luo P, Fu S, Cai H, Ye P, Xiao B, Mao W, Liu L, Yan Y, Liu M, Chen M, Zhang XJ, Wang X, Touyz RM, Xia J, Zhang BH, Huang X, Yuan Y, Loomba R, Liu PP, Li H. Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020 Jun 5;126(12):1671-81.
  • 115. Aleksova A, Ferro F, Gagno G, Cappelletto C, Santon D, Rossi M, Ippolito G, Zumla A, Beltrami AP, Sinagra G. COVID-19 and renin-angiotensin system inhibition: role of angiotensin converting enzyme 2 (ACE2) - is there any scientific evidence for controversy? J Intern Med. 2020 Oct;288(4):410-21.
  • 116. Wysocki J, Ye M, Rodriguez E, González-Pacheco FR, Barrios C, Evora K, Schuster M, Loibner H, Brosnihan KB, Ferrario CM, Penninger JM, Batlle D. Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: prevention of angiotensin II-dependent hypertension. Hypertension. 2010 Jan;55(1):90-8.
  • 117. Chan KK, Dorosky D, Sharma P, Abbasi SA, Dye JM, Kranz DM, Herbert AS, Procko E. Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2. Science. 2020 Sep 4;369(6508):1261-5.
  • 118. Haschke M, Schuster M, Poglitsch M, Loibner H, Salzberg M, Bruggisser M, Penninger J, Krähenbühl S. Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. Clin Pharmacokinet. 2013 Sep;52(9):783-92.
  • 119. Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, Hall R, Poirier G, Ronco JJ, Tidswell M, Hardes K, Powley WM, Wright TJ, Siederer SK, Fairman DA, Lipson DA, Bayliffe AI, Lazaar AL. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017 Sep 7;21(1):234.
  • 120. Hemnes AR, Rathinasabapathy A, Austin EA, Brittain EL, Carrier EJ, Chen X, Fessel JP, Fike CD, Fong P, Fortune N, Gerszten RE, Johnson JA, Kaplowitz M, Newman JH, Piana R, Pugh ME, Rice TW, Robbins IM, Wheeler L, Yu C, Loyd JE, West J. A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. Eur Respir J. 2018 Jun 21;51(6):1702638.
  • 121. Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, Leopoldi A, Garreta E, Hurtado Del Pozo C, Prosper F, Romero JP, Wirnsberger G, Zhang H, Slutsky AS, Conder R, Montserrat N, Mirazimi A, Penninger JM. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020 May 14;181(4):905-913.e7.
  • 122. da Silva Oliveira GL, de Freitas RM. Diminazene aceturate--an antiparasitic drug of antiquity: advances in pharmacology & therapeutics. Pharmacol Res. 2015 Dec;102:138-57.
  • 123. Rajapaksha IG, Mak KY, Huang P, Burrell LM, Angus PW, Herath CB. The small molecule drug diminazene aceturate inhibits liver injury and biliary fibrosis in mice. Sci Rep. 2018 Jul 5;8(1):10175.
  • 124. Nicolau LAD, Nolêto IRSG, Medeiros JVR. Could a specific ACE2 activator drug improve the clinical outcome of SARS-CoV-2? A potential pharmacological insight. Expert Rev Clin Pharmacol. 2020 Aug;13(8):807-11.
  • 125. Murugesan P, Jung B, Lee D, Khang G, Doods H, Wu D. Kinin B1 receptor inhibition with BI113823 reduces inflammatory response, mitigates organ injury, and improves survival among rats with severe sepsis. J Infect Dis. 2016 Feb 15;213(4):532-40.
  • Availability of data and materials

    Not applicable.
  • Funding

    This work was supported by the JBS - “Fazer o bem faz bem” Program and Fundação de Apoio à Universidade Federal de São Paulo (Fap-UNIFESP proc. no. 1424).
  • Ethics approval

    Not applicable.
  • Consent for publication

    Not applicable.

Publication Dates

  • Publication in this collection
    06 Dec 2021
  • Date of issue
    2021

History

  • Received
    15 Jan 2021
  • Accepted
    24 Mar 2021
Centro de Estudos de Venenos e Animais Peçonhentos (CEVAP/UNESP) Av. Universitária, 3780, Fazenda Lageado, Botucatu, SP, CEP 18610-034, Brasil, Tel.: +55 14 3880-7693 - Botucatu - SP - Brazil
E-mail: editorial.jvatitd@unesp.br