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In light of the outbreak of the 2019 novel coronavirus disease (COVID-19), the international scientific community has joined forces to develop effective treatment strategies. The Angiotensin-Converting Enzyme (ACE) 2, is an essential receptor for cell fusion and engulfs the SARS coronavirus infections. ACE2 plays an important physiological role, practically in all the organs and systems. Also, ACE2 exerts protective functions in various models of pathologies with acute and chronic inflammation. While ACE2 downregulation by SARS-CoV-2 spike protein leads to an overactivation of Angiotensin (Ang) II/AT1R axis and the deleterious effects of Ang II may explain the multiorgan dysfunction seen in patients. Specifically, the role of Ang II leading to the appearance of Macrophage Activation Syndrome (MAS) and the cytokine storm in COVID-19 is discussed below. In this review, we summarized the latest research progress in the strategies of treatments that mainly focus on reducing the Ang II-induced deleterious effects rather than attenuating the virus replication., Graphical abstract ACE2 Downregulation in severe COVID-19 patient and appearance of MAS.Unlabelled Image, Highlights • Protective role of ACE2 in the organs and system • Downregulation of ACE2 expression by SARS-CoV-2 leads to Ang II-induced organ damage. • The appearance of MAS in COVID-19 patient • Suggested treatment to diminish the deleterious effect of Ang II or appearance of MAS