The role of kallikrein-kinin and renin-angiotensin systems in COVID-19 infection

Abstract

In November 2019 the first cases of a novel acute respiratory syndrome has been reported in Wuhan province, China. Soon after, in January 2020 the World Health Organization declared a pandemic state due to the dissemination of a virus named SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID-19). Being an unknown disease, it is essential to assess not only its main characteristic features and overall clinical symptomatology but also its patient infection mode and propagation to design appropriate clinical interventions and treatments. In this review the pathophysiology of SARS-CoV-2 infection and how the virus enters the cells and activates the immune system are described. The role of three systems involved in the SARS- CoV-2 infection (renin-angiotensin, kinin and coagulation systems) is discussed with the objectives to identify and try to explain several of the events observed during the evolution of the disease and to suggest possible targets for therapeutic interventions.

Keywords: COVID-19; Coagulation system; Kallikrein-kinin system; Kinins; Renin-angiotensin system.

Graphical abstract

Fig. 1

Hypothetical mechanism by which SARS-CoV-2 successfully evade the immune system while maintaining an inflammatory feedback loop. Following infection coronaviruses remain highly pathogenic at least in part due to the various viral mechanisms allowing them to evade and suppress the IFN response. The CoVs interfere with several processes in innate antiviral immunity. The SARS-CoV-2 can inhibit pattern recognition receptors (PPRs) and/or reduce IFN-I/III levels. ADAM17 (a desintegrin and metalloproteinase 17)-mediated proteolytic cleavage of ACE2 is upregulated by endocytosed SARS-CoV-2 viral particle, that results in over-production of angiotensin II (Angio II) by the related enzyme ACE. The elevate angiotensin II levels increase the activity of angiotensin 1 receptors (AT1R) as found in conditions like fibrosis and inflammation as well as increase reactive oxygen species (ROS) formation and vasoconstriction. In turn, increased angiotensin II enhances IL-6 production via JAK/STAT pathway, thus establishing a positive feedback loop. Moreover, the angiotensin II/AT1 receptor axis activates ADAM17 that cleaves and inactivates ACE2, enhancing angiotensin II levels. In addition, ADAM17 induction also cleaves the membrane form of IL-6Rα to the soluble form (sIL-6Rα), followed by the gp130-mediated activation of STAT, further amplifying the IL-6 signal. The SARS-CoV-2 can also activate NF-κB signaling pathway through increased IκB degradation, a process that leads to the transcription of several pro-inflammatory cytokines that results in what is called a cytokine storm.

Fig. 2

The interplay between renin-angiotensin, kallikrein-kinin and coagulation system activation during COVID infection. Renin cleaves the angiotensinogen into angiotensin I that can be converted to angiotensin II by the angiotensin converting enzyme (ACE or kininase II). Both angiotensin I and II can also be cleaved by angiotensin converting enzyme II (ACE 2) into angiotensin (1-9) and angiotensin (1-7) respectively. Angiotensin II will activate receptors (AT1) which leads to oxidative stress, inflammation, increase in blood pressure due to a vasoconstriction whereas the angiotensin (1-7) will produce vasodilation and potentiates the effects of bradykinin). Lysyl-bradykinin (LBK) and bradykinin (BK) produced after plasma kallikrein cleavage of low or high molecular weight kininogen (LMW or HMW kininogen) respectively, will: 1) directly activate the B2 receptors; 2) be cleave by the kininase I leading to the metabolites lys-desArg⁹BK and desArg⁹BK (B1 receptor agonists). LBK can also be converted to BK through an aminopeptidase action. Activation of B1 or B2 receptors will culminate in inflammatory events exacerbated by the cytokine storm. In the coagulation cascade, the Hageman factor can activate factor XII and convert plasminogen into plasmin which leads to fibrinolysis and clot formation. ACE = angiotensin converting enzyme; ACE2=angiotensin converting enzyme 2; NPE = neutral endopeptidase; HMW kininogen = high molecular weight kininogen; LMW kininogen = low molecular weight kininogen; LBK = lysil-bradykinin; BK = bradykinin. Created with BioRender.com.