A comprehensive insight into the role of zinc deficiency in the renin-angiotensin and kinin-kallikrein system dysfunctions in COVID-19 patients

Hypozincemia is prevalent in severe acute respiratory syndrome coronavirus-2 (SARS-COV-2)-infected patients and has been considered as a risk factor in severe coronavirus disease-2019 (COVID-19). Whereas zinc might affect SARS-COV-2 replication and cell entry, the link between zinc deficiency and COVID-19 severity could also be attributed to the effects of COVID-19 on the body metabolism and immune response. Zinc deficiency is more prevalent in the elderly and patients with underlying chronic diseases, with established deleterious consequences such as the increased risk of respiratory infection. We reviewed the expected effects of zinc deficiency on COVID-19-related pathophysiological mechanisms focusing on both the renin-angiotensin and kinin-kallikrein systems. Mechanisms and effects were extrapolated from the available scientific literature. Zinc deficiency alters angiotensin-converting enzyme-2 (ACE2) function, leading to the accumulation of angiotensin II, des-Arg9-bradykinin and Lysdes-Arg9-bradykinin, which results in an exaggerated pro-inflammatory response, vasoconstriction and pro-thrombotic effects. Additionally, zinc deficiency blocks the activation of the plasma contact system, a protease cascade initiated by factor VII activation. Suggested mechanisms include the inhibition of Factor XII activation and limitation of high-molecular-weight kininogen, prekallikrein and Factor XII to bind to endothelial cells. The subsequent accumulation of Factor XII and deficiency in bradykinin are responsible for increased production of inflammatory mediators and marked hypercoagulability, as typically observed in COVID-19 patients. To conclude, zinc deficiency may affect both the renin-angiotensin and kinin-kallikrein systems, leading to the exaggerated inflammatory manifestations characteristic of severe COVID-19. (c) 2021 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Zinc deficiency in COVID-19 may lead to abnormal activation of the renin-angiotensin and kinin-kallikrein systems, resulting in exaggerated inflammatory manifestations.