Covid-19: the renin-angiotensin system imbalance hypothesis
Katharina Lanza, Lucas G Perez, Larissa B Costa, Thiago M Cordeiro, Vitria A Palmeira, Victor T Ribeiro, Ana Cristina Simões E Silva, Katharina Lanza, Lucas G Perez, Larissa B Costa, Thiago M Cordeiro, Vitria A Palmeira, Victor T Ribeiro, Ana Cristina Simões E Silva
Abstract
The emergency of SARS-CoV-2 in China started a novel challenge to the scientific community. As the virus turns pandemic, scientists try to map the cellular mechanisms and pathways of SARS-CoV-2 related to the pathogenesis of Coronavirus Disease 2019 (Covid-19). After transmembrane angiotensin-converting enzyme 2 (ACE2) has been found to be SARS-CoV-2 receptor, we hypothesized an immune-hematological mechanism for Covid-19 based on renin-angiotensin system (RAS) imbalance to explain clinical, laboratory and imaging findings on disease course. We believe that exaggerated activation of ACE/Angiotensin II (Ang II)/Angiotensin Type 1 (AT1) receptor RAS axis in line with reduction of ACE2/Angiotensin-(1-7)/Mas receptor may exert a pivotal role in the pathogenesis of Covid-19. In this perspective, we discuss potential mechanisms and evidence on this hypothesis.
Keywords: Angiotensin-Converting Enzyme 2; Covid-19; Renin-Angiotensin System; SARS-CoV-2.
Conflict of interest statement
The authors declare that there are no competing interests associated with the manuscript.
© 2020 The Author(s).
Figures
References
- Touyz R., Li H. and Delles C. (2020) ACE2 the Janus-faced protein – from cardiovascular protection to severe acute respiratory syndrome-coronavirus and COVID-19. Clin. Sci. 134, 747–750 10.1042/CS20200363
- Guan W., Ni Z., Hu Y., Liang W., Ou C., He J. et al. . (2020) Clinical Characteristics of Coronavirus Disease 2019 in China. N. Engl. J. Med. 382, 1708–1720 10.1056/NEJMoa2002032
- Nair H., Nokes D., Gessner B., Dherani M., Madhi S., Singleton R. et al. . (2010) Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet North Am. Ed. 375, 1545–1555 10.1016/S0140-6736(10)60206-1
- Wang Q., Zhang Y., Wu L., Niu S., Song C., Zhang Z. et al. . (2020) Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell 181, 894.e9–904.e9 10.1016/j.cell.2020.03.045
- Shang J., Ye G., Shi K., Wan Y., Luo C., Aihara H. et al. . (2020) Structural basis of receptor recognition by SARS-CoV-2. Nature 581, 221–224 10.1038/s41586-020-2179-y
- Nehme A., Cerutti C., Dhaouadi N., Gustin M., Courand P., Zibara K. et al. . (2015) Atlas of tissue renin-angiotensin-aldosterone system in human: A transcriptomic meta-analysis. Sci. Rep. 5, 10.1038/srep10035
- Rodrigues Prestes T., Rocha N., Miranda A., Teixeira A. and Simoes-e-Silva A. (2017) The Anti-Inflammatory Potential of ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Evidence from Basic and Clinical Research. Curr. Drug Targets 18, 10.2174/1389450117666160727142401
- Imai Y., Kuba K., Rao S., Huan Y., Guo F., Guan B. et al. . (2005) Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 436, 112–116 10.1038/nature03712
- Siddiqi H. and Mehra M. (2020) COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal. J. Heart Lung Transplant. 39, 405–407 10.1016/j.healun.2020.03.012
- Kuba K., Imai Y., Rao S., Gao H., Guo F., Guan B. et al. . (2005) A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat. Med. 11, 875–879 10.1038/nm1267
- Fang Y., Gao F. and Liu Z. (2019) Angiotensin-converting enzyme 2 attenuates inflammatory response and oxidative stress in hyperoxic lung injury by regulating NF-κB and Nrf2 pathways. QJM 112, 914–924 10.1093/qjmed/hcz206
- AlGhatrif M., Cingolani O. and Lakatta E. (2020) The Dilemma of Coronavirus Disease 2019, Aging, and Cardiovascular Disease. JAMA Cardiol. 10.1001/jamacardio.2020.1329
- Zheng Y., Ma Y., Zhang J. and Xie X. (2020) Reply to: ‘Interaction between RAAS inhibitors and ACE2 in the context of COVID-19. Nat. Rev. Cardiol. 17, 313–314 10.1038/s41569-020-0369-9
- Guo J., Huang Z., Lin L. and Lv J. (2020) Coronavirus Disease 2019 (COVID‐19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin‐Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. J. Am. Heart Assoc. 9
- Wang X., Xu W., Hu G., Xia S., Sun Z., Liu Z. et al. . (2020) SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion. Cell. Mol. Immunol., 10.1038/s41423-020-0424-9
- Joshi S., Wollenzien H., Leclerc E. and Jarajapu Y. (2019) Hypoxic regulation of angiotensin‐converting enzyme 2 and Mas receptor in human CD34 + cells. J. Cell. Physiol. 234, 20420–20431 10.1002/jcp.28643
- Mehta P., McAuley D., Brown M., Sanchez E., Tattersall R. and Manson J. (2020) COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet North Am. Ed. 395, 1033–1034 10.1016/S0140-6736(20)30628-0
- Simões e Silva A., Silveira K., Ferreira A. and Teixeira M. (2013) ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. Br. J. Pharmacol. 169, 477–492 10.1111/bph.12159
- Wenzhong l. and Hualan L. (2020) COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism
- Gattinoni L., Coppola S., Cressoni M., Busana M., Rossi S. and Chiumello D. (2020) COVID-19 Does Not Lead to a “Typical” Acute Respiratory Distress Syndrome. Am. J. Respir. Crit. Care Med. 201, 1299–1300 10.1164/rccm.202003-0817LE
- Sardu C., Gambardella J., Morelli M., Wang X., Marfella R. and Santulli G. (2020) Is COVID-19 an Endothelial Disease? Clin. Basic Evidence
- Tanaka T., Narazaki M. and Kishimoto T. (2014) IL-6 in Inflammation, Immunity, and Disease. Cold Spring Harb. Perspect. Biol. 6, a016295–a016295 10.1101/cshperspect.a016295
- Liu Q., Zhou Y. and Yang Z. (2015) The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell. Mol. Immunol 13, 3–10
- Channappanavar R. and Perlman S. (2017) Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin. Immunopathol. 39, 529–539 10.1007/s00281-017-0629-x
- Sahraei Z., Shabani M., Shokouhi S. and Saffaei A. (2020) Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine. Int. J. Antimicrob. Agents 55, 105945 10.1016/j.ijantimicag.2020.105945
- Nikpouraghdam M., Jalali Farahani A., Alishiri G., Heydari S., Ebrahimnia M., Samadinia H. et al. . (2020) Epidemiological characteristics of coronavirus disease 2019 (COVID-19) patients in IRAN: A single center study. J. Clin. Virol. 127, 104378 10.1016/j.jcv.2020.104378
- Jin J., Bai P., He W., Wu F., Liu X., Han D. et al. . (2020) Gender Differences in Patients With COVID-19: Focus on Severity and Mortality. Front. Public Health 8, 10.3389/fpubh.2020.00152
- Xudong X., Junzhu C., Xingxiang W., Furong Z. and Yanrong L. (2006) Age- and gender-related difference of ACE2 expression in rat lung. Life Sci. 78, 2166–2171 10.1016/j.lfs.2005.09.038
- Colafella K., Hilliard L. and Denton K. (2016) Epochs in the depressor/pressor balance of the renin–angiotensin system. Clin. Sci. 130, 761–771 10.1042/CS20150939
- Kaschina E., Namsolleck P. and Unger T. (2017) AT2 receptors in cardiovascular and renal diseases. Pharmacol. Res. 125, 39–47 10.1016/j.phrs.2017.07.008
Source: PubMed