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

Figures

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  Figure 1. Pathways of interaction between the kallikrein-kinin and renin-angiotensin-aldosterone systems and mechanism of action of angiotensin converting enzyme (ACE) inhibitors (ACEI) and angiotensin type 1 (AT1) receptor blockers (ARB). Kininogen, the precursor of kallikrein-kinin system is cleaved by kallikrein-releasing bradykinin that acts mainly on B2R promoting the effects described in the box. Then, bradykinin is degraded by ACE or can be converted to DABK by CPM and CPN, DABK is an agonist of B1 receptor, subsequently ACE2 can inactivate DABK. In renin-angiotensin-aldosterone system, the precursor angiotensinogen is processed by renin-releasing angiotensin I, which can be cleaved by ACE to form angiotensin II that exerts its effects by binding to AT1 and AT2. Ang II is substrate for ACE2 generating angiotensin 1-7, an active peptide that exerts protective effects binding to Mas. ACEI acts by inhibiting ACE, consequently ACEIs inhibit Ang II formation and Ang 1-7 and BK degradation, these effects combined promote vasodilation. ARBs, blockers that act specifically on AT1R, inhibit Ang II binding to AT1R and its effects. Also, they possibly trigger intracellular acidification that…

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  Figure 2. Schematic of COVID-19 outcomes on the renin-angiotensin-aldosterone and kallikrein-kinin systems, and proposed therapies with RAAS blockers, B1R and recombinant sACE2. (I) SARS-CoV-2/ACE2 complex is internalized by endocytosis, (II) triggering viral replication and reduction of transmembrane ACE2, which provokes (IIIa) the imbalance of RAAS and KKS, with (IIIb) Ang II/AT1R and DABK/B1R pathway activation, respectively. (IVa) Ang II/AT1R upregulation induces ADAM-17 activation, which is responsible for (V) ACE2 shedding that can contribute to depletion of ACE2 local effects, in addition (IVb) Ang II/AT1R promotes inflammatory and fibrotic processes. (IVc) DABK/B1R upregulation also triggers pro-inflammatory cascades. It is pointed out the actions of RAAS blockers (ACEI and ARB), ACE2 activators and B1R antagonists, counterbalancing the deleterious effects of downregulation of ACE2 in SARS-CoV-2 infection. In detail, (VI) the effect of sACE2 recombinant as therapy, that act as a competitive interceptor of SARS-CoV-2 by preventing binding of coronavirus to the surface-bound, besides providing increased Ang 1-7 circulating levels. ACEI: angiotensin-converting enzyme inhibitors; ACE2:…