The RAAS Axis and SARS-CoV-2: From Oral to Systemic Manifestations

Abstract

One of the essential regulators of arterial blood pressure, the renin-angiotensin-aldosterone system (RAAS) seems to be one of the most complex mechanisms in the human body. Since the discovery of its key components and their actions, new substances and functions are still being unraveled. The main pathway begins with the secretion of renin in the kidney and culminates with the synthesis of angiotensin II (Ang II)-a strong vasoconstrictor-thanks to the angiotensin-converting enzyme (ACE). Research conducted in 2000 identified another enzyme, named ACE2, that converts Ang II into Ang-(1-7), a heptapeptide with opposing effects to those of Ang II: vasodilation and anti-inflammatory properties. This particular enzyme became of paramount importance during the last two decades, as a result of the confrontation of the human race with life-threatening epidemics. Multiple studies have been performed in order to uncover the link between ACE2 and human coronaviruses, the results of which we systemized in order to create an overview of the pathogenic mechanism. Human coronaviruses, such as SARS-CoV and SARS-CoV-2, attach to ACE2 via their spike proteins (S), causing the destruction of the enzyme. Because ACE2 limits the production of Ang II (by converting it into Ang-(1-7)), its destruction leads to a dysregulated inflammatory response. The purpose of this review is to decipher the complex pathophysiological mechanisms underlying the multiorgan complications (oral, cardiac, pulmonary, systemic) that appear as a result of the interaction of the SARS CoV-2 virus with the angiotensin-converting enzyme type 2.

Keywords: ACE2; COVID-19; RAAS; SARS-CoV-2.

Figure 1

The renin-angiotensin system. ACE, angiotensin converting enzyme; ACE, angiotensin converting enzyme 2; Ang, angiotensin; ALD, aldosterone; ADH, antidiuretic hormone. Green boxes indicate the pro-inflammatory pathway, while purple boxes indicate the anti-inflammatory arm (adapted after [4,6]).

Figure 2

Effects of aldosterone in the kidney. MR, mineralocorticoid receptor; ATP, Na⁺-K⁺ ATP-ase (pump); ENaC, epithelial Na⁺ channels (adapted after [6]).

Figure 3

Structure of human coronaviruses. S, spike protein; E, envelope protein; M, membrane protein; N, nucleocapsid protein; +RNA, genome (adapted after [32]).

Figure 4

SARS-CoV-2 spike (S) protein domain structure (with two subunits, S1 and S2) and cleavage sites. TMPRSS2, transmembrane serine protease 2 (adapted after [45]).

Figure 5

The interaction between the receptor binding domain (RBD) of the S1 subunit and angiotensin converting enzyme 2 (ACE2) (adapted after [45]).

Figure 6

SARS-CoV-2 entry and replication cycle. L, RNA polymerase; ER, endoplasmic reticulum. 1—binding to ACE2 and viral entry via endocytosis; 2—release of viral genome; 3—translation of L protein; 4—RNA replication; 5—transcription of viral genome and proteins; 6—translation of N protein and assembly of nucleocapsid in cytoplasm; 7—translation of S, M and E proteins in the ER; 8—combining of S, M and E proteins with the nucleocapsid in the Golgi body; 9—formation of mature virion; 10, exocytosis (adapted after [32]).

Figure 7

Effects of the interaction between increased Ang II levels and AT₁R. TNFR, TNF-α receptor; EGFR, EGF receptor; IL-6 AMP, IL-6 amplifier; ARDS, acute respiratory distress syndrome. (adapted after [46]).

Figure 8

Laboratory and clinical profiles and key mechanisms of systemic inflammation and hyp-ercoagulation in COVID-19. aPTT—activated partial thromboplastin time; ESR—erythrocyte sedimentation rate (adapted after [58]).

Figure 9

The coagulation cascade. PolyP, polyphosphate; TF, tissue factor (adapted after [1]).

Figure 10

Physiological anticoagulants. S-C denotes the interaction of protein C with its cofactor, protein S (adapted after [1]).

Figure 11

Laboratory and clinical profiles and key mechanisms of systemic manifestations of COVID-19.O₂—oxygen; BNP– brain natriuretic peptide; ALT—alanine transaminase; AST—aspartate transaminase; LDH—lactate dehydrogenase (adapted after [58]).