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.

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