Interactions amongst inflammation, renin-angiotensin-aldosterone and kallikrein-kinin systems: suggestive approaches for COVID-19 therapy

Abstract

Coronavirus disease 2019 (COVID-19) is a rapid-spread infectious disease caused by the SARS-CoV-2 virus, which can culminate in the renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin (KKS) systems imbalance, and in serious consequences for infected patients. This scoping review of published research exploring the RAAS and KKS was undertaken in order to trace the history of the discovery of both systems and their multiple interactions, discuss some aspects of the viral-cell interaction, including inflammation and the system imbalance triggered by SARS-CoV-2 infection, and their consequent disorders. Furthermore, we correlate the effects of continued use of the RAAS blockers in chronic diseases therapies with the virulence and physiopathology of COVID-19. We also approach the RAAS and KKS-related proposed potential therapies for treatment of COVID-19. In this way, we reinforce the importance of exploring both systems and the application of their components or their blockers in the treatment of coronavirus disease.

Dysregulated Bradykinin: Mystery in the Pathogenesis of COVID-19

“…Then, kininase II, a tripeptidase, known as angiotensin-converting enzyme (ACE) also acts through a similar mechanism to inactivate bradykinin ( Figure 1 ) [ 19 ]. Bradykinin is cleaved also by serine proteases, prolyl endopeptidases, and aminopeptidases [ 20 , 21 ].…”

“…BK receptors are G-protein coupled cell surface receptors, and these are the bradykinin 1 receptor (B1R) and bradykinin 2 receptor (B2R). BK, as well as DABK, preferentially acts through these receptors, and BK acts as a ligand for B2R, while DABK is the main agonist for B1R [ 3 , 21 ].…”

“…In addition, B2R forms dimers with many of the renin angiotensin aldosterone system (RAAS) receptors that are important in regulating physiologic functions, including thrombosis risk regulation. B2R forms complexes with endothelial nitric oxide synthase (eNOS, NOS3), while B1R interacts with the cytokine-inducible nitric oxide synthase (iNOS, NOS2) [ 21 ].…”

“…PGE2 (prostaglandin E2) produced by BK activation also releases renin. This function of BK helps in interaction between RAAS and KKS [ 21 ].…”

“…KKS is associated with the increased vascular permeability and inflammatory response during various viral infections [ 21 ]. Formation of microthrombi is another important symptom seen in COVID-19 patients.…”