COVID-19 and the renin-angiotensin system (RAS): A spark that sets the forest alight?

O J Wiese, B W Allwood, A E Zemlin, O J Wiese, B W Allwood, A E Zemlin

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has increased exponentially in numbers with more than 20 million people infected around the globe. It is clear that COVID-19 is not a simple viral pneumonia, but presents with unusual pathophysiological effects. Of special interest is that SARS-CoV-2 utilises the angiotensin-converting enzyme-2 (ACE2) for cell entry and therefore has a direct effect on the renin angiotensin system (RAS). The RAS is primarily responsible for blood pressure control via the classic pathway. Recently numerous other pathological processes have been described due to stimulation of this classic pathway. There is also a protective RAS pathway medicated by ACE2 which may be suppressed in COVID-19. This leads to overstimulation of the classic pathway with adverse cardiovascular and respiratory effects, hypercoagulation, endothelial dysfunction, inflammation and insulin resistance. We hypothesize that overreaction of the renin-angiotensin-aldosterone may account for the myriad of unusual biochemical and clinical abnormalities noted in patients infected with SARS-CoV-2.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Fig. 1
Fig. 1
The RAS pathway showing the classical and protective arms as well as the various receptors and their downstream effects. RAS: Renin Angiotensin System. ACEi: Angiotensin Converting Enzyme inhibitor. ARB: Angiotensin Receptor Blocker. AT1: Angiotensin 1 receptor. AT2: Angiotensin 2 receptor.

References

    1. Yang T., Xu C. Physiology and pathophysiology of the intrarenal renin-angiotensin system: an update. J Am Soc Nephrol. 2017;28(4):1040–1049.
    1. Paz Ocaranza M., Riquelme J.A., García L., Jalil J.E., Chiong M., Santos R.A.S. Counter-regulatory renin-angiotensin system in cardiovascular disease. Nat Rev Cardiol. 2020;17(2):116–129. doi: 10.1038/s41569-019-0244-8.
    1. Dhanachandra Singh K., Karnik S.S. Angiotensin receptors: structure, function, signaling and clinical applications. J Cell Signal. 2017;01(02) Available from:
    1. Carey RM. Update on angiotensin AT2 receptors. Vol. 26, Current Opinion in Nephrology and Hypertension. Lippincott Williams and Wilkins; 2017. p. 91–6.
    1. Imai Y., Kuba K., Rao S., Huan Y., Guo F., Guan B. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112–116.
    1. Underwood P.C., Adler G.K. The renin angiotensin aldosterone system and insulin resistance in humans. Curr Hypertens Rep. 2013;15(1):59–70. Available from: .
    1. Dominici F.P., Burghi V., Muñoz M.C., Giani J.F. Modulation of the action of insulin by angiotensin-(1-7) Clin Sci. 2014;126:613–630.
    1. Li W., Moore M.J., Vasllieva N., Sui J., Wong S.K., Berne M.A. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450–454.
    1. Hoffmann M., Kleine-Weber H., Schroeder S., Krüger N., Herrler T., Erichsen S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271–280.e8.
    1. Oudit G.Y., Kassiri Z., Jiang C., Liu P.P., Poutanen S.M., Penninger J.M. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest. 2009;39(7):618–625.
    1. Hamming I., Timens W., Bulthuis M.L.C., Lely A.T., Navis G.J., van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631–637.
    1. Kuba K., Imai Y., Penninger J.M. Angiotensin-converting enzyme 2 in lung diseases. Curr Opin Pharmacol. 2006;6(3):271–276.
    1. Arentz M., Yim E., Klaff L., Lokhandwala S., Riedo F.X., Chong M. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State. JAMA – J Am Med Assoc. 2020;323:1612–1614.
    1. Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Z. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–1062. Available from
    1. Richardson S., Hirsch J.S., Narasimhan M., Crawford J.M., McGinn T., Davidson K.W. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA – J Am Med Assoc. 2020;323(20):2052–2059.
    1. Grasselli G., Zangrillo A., Zanella A., Antonelli M., Cabrini L., Castelli A. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA – J Am Med Assoc. 2020;323(16):1574–1581.
    1. Klok F.A., Kruip M.J.H.A., van der Meer N.J.M., Arbous M.S., Gommers D.A.M.P.J., Kant K.M. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191 Available from:
    1. Bikdeli B., Madhavan M.V., Jimenez D., Chuich T., Dreyfus I., Driggin E. COVID-19 and Thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am College Cardiol. 2020;75:2950–2973.
    1. Gibson W.T., Evans D.M., An J., Jones S.J. ACE 2 Coding variants: a potential X-linked risk factor for COVID-19 disease. bioRxiv. 2020;2020(4646116)
    1. Xudong X., Junzhu C., Xingxiang W., Furong Z., Yanrong L. Age- and gender-related difference of ACE2 expression in rat lung. Life Sci. 2006;78(19):2166–2171.
    1. Kuba K., Imai Y., Rao S., Gao H., Guo F., Guan B. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875–879.
    1. Mancini G.B.J., Khalil N. Angiotensin II type 1 receptor blocker inhibits pulmonary injury. Clin Invest Med. 2005;28(3):118–126. Available from: .
    1. Mehta P., McAuley D.F., Brown M., Sanchez E., Tattersall R.S., Manson J.J. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–1034. doi: 10.1016/S0140-6736(20)30628-0.
    1. Jin Y, Yang H, Ji W, Wu W, Chen S, Zhang W, et al. Virology, epidemiology, pathogenesis, and control of covid-19. Vol. 12, Viruses. MDPI AG; 2020.
    1. Ruan Q., Yang K., Wang W., Jiang L., Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan China. Intensive Care Med. 2020;46(5):846–848. doi: 10.1007/s00134-020-05991-x.
    1. Larina V., Golovko M., Larin V. Possible effects of coronavurus infection (COVID-19) on the cardiovascular system. Bull Russ State Med Univ. 2020;2
    1. Liu F., Li L., Da X.M., Wu J., Luo D., Zhu Y.S. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol. 2020;1:127.
    1. Dandona P., Dhindsa S., Ghanim H., Chaudhuri A. Angiotensin II and inflammation: The effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. J Hum Hypertens. 2007;21(1):20–27.
    1. Connors J.M., Levy J.H. Thromboinflammation and the hypercoagulability of COVID-19. J Thrombosis Haemostasis. 2020
    1. Lillicrap D. Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia. J Thrombosis Haemostasis. 2020;18:786–787.
    1. Gromotowicz-Poplawska A., Stankiewicz A., Kramkowski K., Gradzka A., Wojewodzka-Zelezniakowicz M., Dzieciol J. The acute prothrombotic effect of aldosterone in rats is partially mediated via angiotensin II receptor type 1. Thromb Res. 2016;138:114–120. doi: 10.1016/j.thromres.2015.12.008.
    1. Sawathiparnich P., Murphey L.J., Kumar S., Vaughan D.E., Brown N.J. Effect of combined AT1 receptor and aldosterone receptor antagonism on plasminogen activator inhibitor-1. J Clin Endocrinol Metab. 2003;88(8):3867–3873.
    1. Ducros E., Berthaut A., Mirshahi S.S., Faussat A.M., Soria J., Agarwal M.K. Aldosterone modifies hemostasis via upregulation of the protein-C receptor in human vascular endothelium. Biochem Biophys Res Commun. 2008;373(2):192–196.
    1. Remková A., Remko M. The role of renin-angiotensin system in prothrombotic state in essential hypertension. Physiol Res. 2010;59:13–23.
    1. Liu Y., Yang Y., Zhang C., Huang F., Wang F., Yuan J. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364–374.
    1. Vaduganathan M., Vardeny O., Michel T., McMurray J.J.V., Pfeffer M.A., Solomon S.D. Renin-angiotensin-aldosterone system inhibitors in patients with covid-19. N Engl J Med. 2020;382(17):1653–1659.
    1. Zemlin A.E., Wiese O.J. ANNALS EXPRESS: Coronavirus disease 2019 (COVID-19) and the renin-angiotensin system: a closer look at angiotensin-converting enzyme 2 (ACE2) Ann Clin Biochem. 2020;2019
    1. HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19 – American College of Cardiology [Internet]. [cited 2020 Jul 16]. Available from: .
    1. Danser A.H.J., Epstein M., Batlle D. Renin-Angiotensin system blockers and the COVID-19 pandemic: at present there is no evidence to abandon renin-angiotensin system blockers. Hypertension. 2020;75:1382–1385. Available from:
    1. Batlle D., Wysocki J., Satchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? Clin Sci. 2020;134(5):543–545.
    1. Wang K., Gheblawi M., Oudit G.Y. Angiotensin converting enzyme 2: a double-edged sword. Circulation. 2020
    1. Busse L.W., Chow J.H., McCurdy M.T., Khanna A.K. COVID-19 and the RAAS – a potential role for angiotensin II? Critical Care. 2020;24 Available from:
    1. South A.M., Diz D.I., Chappell M.C. COVID-19, ACE2, and the cardiovascular consequences. Am J Physiol Heart Circ Physiol. 2020;318(5):H1084–H1090.
    1. Peiró C., Moncada S. Substituting angiotensin-(1-7) to prevent lung damage in SARSCoV2 infection? Circulation. 2020;141(21):1665–1666.

Source: PubMed

3
Abonnere