Kinins and chymase: the forgotten components of the renin-angiotensin system and their implications in COVID-19 disease

Abstract

The unique clinical features of COVID-19 disease present a formidable challenge in the understanding of its pathogenesis. Within a very short time, our knowledge regarding basic physiologic pathways that participate in SARS CoV-2 invasion and subsequent organ damage have been dramatically expanded. In particular, we now better understand the complexity of the renin-angiotensin-aldosterone system (RAAS) and the important role of angiotensin converting enzyme (ACE)-2 in viral binding. Furthermore, the critical role of its major product, angiotensin (Ang) 1-7, in maintaining microcirculatory balance and in the control of activated pro-inflammatory and pro-coagulant pathways, generated in this disease, have been clarified. The kalikrein-bradykinin (BK) system and chymase are intensively interwoven with RAAS through many pathways with complex reciprocal interactions. Yet, so far, very little attention has been paid to a possible role of these physiologic pathways in the pathogenesis of COVID-19 disease, even though BK and chymase exert many physiologic changes characteristic to this disorder. Herein we outline the current knowledge regarding the reciprocal interactions of RAAS, BK and chymase that are probably turned-on in COVID-19 disease and participate in its clinical features. Interventions affecting these systems, such as the inhibition of chymase or blocking BKB1R/BKB2R might be explored as potential novel therapeutic strategies in this devastating disorder.

Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?

“…However, in rat models of thrombosis, even Ang (1–9) has been shown to induce both arterial thrombotic platelet aggregation and impairment of fibrinolysis (enhancing venous thrombosis) via Ang II/AT1R axis ( Kramkowski et al, 2010 ; Mogielnicki et al, 2014 ), thus suggesting that ACE2-produced Ang (1–9) could synergistically work with Ang II in inducing thrombotic/ischemic processes at late and severe stages of COVID-19. In addition, recent reports ( Abassi et al, 2021 ; S. Zhang et al, 2020 ), showing that ACE2 is expressed by platelets, suggest that SARS-CoV-2 virions can bind platelets, finally inducing platelet activation that may participate not only in thrombus formation but also in systemic sACE2 release.…”

“…Moreover, activation of BKB1R mediated by attenuation of pulmonary ACE2 activity has been shown to exacerbate inflammation by inducing further release of proinflammatory cytokines and promoting lung neutrophil infiltration ( Sodhi et al, 2018 ). For these reasons, several reports have suggested the involvement of the KKS in COVID-19 ( Abassi et al, 2021 ; De Maat et al, 2020 ; Garvin et al, 2020 ; Tolouian et al, 2020 ; van de Veerdonk et al, 2020 ). However, most reports hypothesised an enhanced Arg(9)-BK/BKB1R signalling due to a SARS-CoV-2-induced downregulation of ACE2 activity ( Abassi et al, 2021 ; De Maat et al, 2020 ; Tolouian et al, 2020 ).…”

“…For these reasons, several reports have suggested the involvement of the KKS in COVID-19 ( Abassi et al, 2021 ; De Maat et al, 2020 ; Garvin et al, 2020 ; Tolouian et al, 2020 ; van de Veerdonk et al, 2020 ). However, most reports hypothesised an enhanced Arg(9)-BK/BKB1R signalling due to a SARS-CoV-2-induced downregulation of ACE2 activity ( Abassi et al, 2021 ; De Maat et al, 2020 ; Tolouian et al, 2020 ). Instead, ACE2 upregulation was recently revealed; therefore, an increased inactivation of Arg(9)-BK should lead to switch off BKR1R inflammatory pathway, at least during the early phase of COVID-19.…”

Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic

“…It is noteworthy that, as detailed in depth elsewhere [31], ACE, ACE2 and Ang-(1-7) affect the generation, action, degradation and elimination of bradykinin through complex interwoven mechanisms that may also be involved in the physiological responses to RAS. As a result, at the bottom line, Ang-(1-7) seems to promote [32][33][34] and potentiate the vasodilatory effect of bradykinin [35], exerting vasorelaxation through the endotheliumdependent release of nitric oxide.…”

“…As a result, at the bottom line, Ang-(1-7) seems to promote [32][33][34] and potentiate the vasodilatory effect of bradykinin [35], exerting vasorelaxation through the endotheliumdependent release of nitric oxide. As with RAS, bradykinin exerts opposing physiologic responses by binding to different receptors, and the bradykinin B2 receptors are those mediating vascular relaxation, in concert with MasR and AT2R [26,31] (Figure 1). Finally, there are still gaps of knowledge regarding the RAS system, and newly discovered components such as alatensins are still being studied [3].…”