Papel dos receptores de cininas e seus mediadores inflamatórios e vasodilatadores em células HUVEC e VERO E6 infectadas com SARS-CoV-2

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the etiologic agent of Coronavirus Disease 2019 (COVID-19), the disease responsible for the pandemic that began in 2019 with the first cases and extends to the present day. SARS-CoV-2 binds its spike (S) protein to Angiotensin Converting Enzyme 2 (ACE2) and uses it as an entry receptor into the target cell. This enzyme is present on the cell surface of various organs, such as endothelial cells, lungs, heart, kidneys, and intestine. Infection activates the immune system, releasing pro-inflammatory cytokines such as Interleukin 6 (IL-6), IL-8, Tumor Necrosis Factor α (TNF-α), among others. In addition, the kallikrein-kinin system (KKS) is deregulated, because ACE2 plays an important role in the balance of this system. When entering the host cell, the virus internalizes with it the ACE2, preventing its enzymatic functions in the KKS, and for this reason the deregulation of this system occurs. In the KKS, the ACE2 has the function of inactivating kinesins that are ligands of the B1 receptor (B1R), a receptor expressed in inflammation and that generates effects such as hypotension, increased vascular permeability, and vasodilation. Both B1R and B2 receptor (B2R) binding generates these effects, leading to so-called pulmonary angioedema, i.e., extravasation of fluid into the lungs. All these findings, together with the exacerbated production of proinflammatory cytokines (potentiated by Bradikinin) may be related to disease progression, permanent sequelae, and death. Therefore the present study evaluated the role of B1R and B2R and their inflammatory and vasodilatory mediators in human HUVEC endothelial cell lines and VERO E6 monkey kidney epithelial cell lines infected with SARS-CoV-2. The results demonstrated reduced ACE2, which may confirm the internalization hypothesis of the enzyme. In addition, increased expression of B1R and B2R occurred, as well as increased Bradikinin (BK) production by infected cells. Accordingly, increased IL-6, produced in the inflammatory response of COVID19 and B2R stimulation, was reported. Increased Nitric Oxide (NO) was also demonstrated, which may be generated by both infection and BK production. In summary, our findings may help confirm the role of BK in the pathogenesis of COVID-19, collaborating with severe cases of the disease.