The Controversy on the Role of ACE2 Receptor in COVID-19 Infection: The Protective Shift toward the ACE2 Axis


Background: Angiotensin-converting enzyme 2 (ACE2)  is recognized as the main cellular receptor for the new coronavirus, SARS-CoV-2, that facilitates its entry into the host target cell, leading to the fatal viral infection, coronavirus disease 2019 (COVID-19). Thus, it is considered as a main therapeutic target in the SARS-CoV-2 infection. The dual role of ACE2 as a gate for SARS-CoV-2 virus and as a part of lung and multi-organ protection has built a scientific debate that affects the choice of treatments used against COVID-19 patient. ACE2 inhibitors like anti-ACE2 antibodies were first introduced as therapeutic solutions that, theoretically, would decrease the availability of target molecules for SARS-CoV-2 by downregulating ACE2 expression. However, animal studies showed that ACE2 upregulation acts as a counterbalance to the hypertensive pro-inflammatory angiotensin I-converting enzyme (ACE) in the renin–angiotensin system (RAS) and results in a protective role against acute lung injury – a fatal consequence of the disease. The current study tests the effect of ACE2-activating treatments against the outcome of genetic variations in the population that have ACE2-upregulatory effects.

Conclusion  Despite its role as a receptor for the SARS-CoV-2 virus, experimental studies and the genetic polymorphisms in populations that have ACE2 upregulation revealed a protective role against COVID-19 infection.


Key words: ACE2   ACE  COVID-19  treatments  genetic variations

[1] Zhang, H., Penninger, J. M., Li, Y., et al. (2020). Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Medicine, vol. 46, no. 4, pp. 586–590. Retrieved from

[2] Povlsen, A., Grimm, D., Wehland, M., et al. (2020). The vasoactive mas receptor in essential hypertension. Journal of Clinical Medicine, vol. 9, no. 1, p. 267. Retrieved from

[3] Santos, R. A. S., Sampaio, W. O., Alzamora, A. C., et al. (2018). The ACE2/angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7). Physiological Reviews, vol. 98, no. 1, pp. 505–553. Retrieved from

[4] Dandona, P., Dhindsa, S., Ghanim, H., et al. (2007). Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. Journal of Human Hypertension, vol. 21, no. 1, pp. 20–27. Retrieved from

[5] Tikellis, C. and Thomas, M. C. (2012). Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. International Journal of Peptide Research and Therapeutics, vol. 2012, 256294. Retrieved from

[6] Hoffmann, M., Kleine-Weber, H., Schroeder, S., et al. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, vol. 181, no. 2, pp. 271–280.e8. Retrieved from

[7] Sedokani, A. and Feizollahzadeh, S. (2020). Plasmapheresis, anti-ACE2 and anti-FcγRII monoclonal antibodies: a possible treatment for severe cases of COVID-19. Drug Design, Development and Therapy, vol. 14, pp. 2607–11. Retrieved from

[8] Kuba, K., Imai, Y., Rao, S., et al. (2005). A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nature Medicine, vol. 11, no. 8, pp. 875–879. Retrieved from

[9] Imai, Y., Kuba, K., Rao, S., et al. (2005). Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature, vol. 436, no. 7047, pp. 112–116. Retrieved from

[10] Zoufaly, A., Poglitsch, M., Aberle, J. H., et al. (2020). Human recombinant soluble ACE2 in severe COVID-19. Lancet Respiratory Medicine, vol. 8, no. 11, pp. 1154–1158. Retrieved from

[11] Ursini, F., Ciaffi, J., Landini, M. P., et al. (2020). COVID-19 and diabetes: is metformin a friend or foe? Diabetes Research and Clinical Practice, vol. 164, 108167. Retrieved from

[12] Imai, Y., Kuba, K., and Penninger, J. M. (2008). The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. Experimental Physiology, vol. 93, no. 5, pp. 543–548. Retrieved from

[13] Jia, H. (2016). Pulmonary angiotensin-converting enzyme 2 (ACE2) and inflammatory lung disease. Shock, vol. 46, no. 3, pp. 239–248. Retrieved from

[14] Marshall, R. P., Webb, S., Bellingan, G. J., et al. (2002). Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine, vol. 166, no. 5, pp. 646–650. Retreived from

[15] Adamzik, M., Frey, U., Sixt, S., et al. (2007). ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS. European Respiratory Journal, vol. 29, no. 3, pp. 482–488. Retrieved from

[16] Hatami, N., Ahi, S., Sadeghinikoo, A., et al. (2020). Worldwide ACE (I/D) polymorphism may affect COVID-19 recovery rate: an ecological meta-regression. Endocrine, vol. 68, no. 3, pp. 479–484. Retrieved from

[17] Kenyon, C. (2020). ACE-1 I/D polymorphism associated with COVID-19 incidence and mortality: an ecological study. Preprint, 2020040262. Retrieved from

[18] Srivastava, A., Bandopadhyay, A., Das, D., et al. (2020). Genetic association of ACE2 rs2285666 polymorphism with COVID-19 spatial distribution in India. Frontiers in Genetics, vol. 11, 564741. Retrievd from

[19] Xudong, X., Junzhu, C., Xingxiang, W., et al. (2006). Age- and gender-related difference of ACE2 expression in rat lung. Life Sciences, vol. 78, no. 19, pp. 2166–2171. Retrieved from

[20] Leung, J. M., Yang, C. X., Tam, A., et al. (2020). ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. European Respiratory Journal, vol. 55, no. 5, p. 2000688. Retrieved from

[21] Rockx, B., Baas, T., Zornetzer, G. A., et al. (2009). Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection. Journal of Virology, vol. 83, no. 14, pp. 7062–7074. Retrieved from

[22] Prata, L. O., Rodrigues, C. R., Martins, J. M., et al. (2017). Original Research: ACE2 activator associated with physical exercise potentiates the reduction of pulmonary fibrosis. Experimental Biology and Medicine, vol. 242, no. 1, pp. 8–21. Retrieved from