The Renin-Angiotensin System in COVID-19: Can Long COVID Be Predicted?

Abstract

(1) Background: Co-morbidities such as hypertension and cardiovascular disease are major risk factors for severe COVID-19. The renin-angiotensin system (RAS) is critically involved in their pathophysiology and is counter-balanced by both angiotensin-converting enzyme 2 (ACE2), the functional receptor of SARS-CoV-2, and the kallikrein-kinin system (KKS). Considerable research interest with respect to COVID-19 treatment is currently being directed towards the components of these systems. In earlier studies, we noticed significantly reduced carboxypeptidase N (CPN, KKS member) activity and excessive angiotensin-converting enzyme (ACE, RAS member) activity in the sera of both hospitalized COVID-19 patients and a subgroup of convalescent patients. The data had been obtained using labeled bradykinin (BK) as a reporter peptide, which is a target of both CPN and ACE. The data were supplemented with mass-spectrometry-based serum proteomic analysis. Here, we hypothesize that the degree of BK serum degradation could be indicative of Long COVID. (2) Review and Discussion: The recent literature is briefly reviewed. The fact that the levels of the BK serum degradation products did not reach normal concentrations in almost half of the patients during convalescences could have been partially due to a dysregulated RAS. (3) Conclusions: Standard tests for routine patient care in Long COVID come often back normal. We suggest that the measurement of selected members of the RAS such as ACE and angiotensin II or the use of our BK degradation assay could identify Long COVID candidates. Clinical studies are required to test this hypothesis.

Keywords: ACE; ACE inhibitors; ACE2; CPN; RAS; angiotensin receptor blockers; antihypertensive; bradykinin; cardiovascular disease; hypertension; mass spectrometry; neuropeptide reporter assay.

Figure 1

The connection of the kallikrein–kinin system (KKS) and the renin–angiotensin system (RAS) with respect to intervention by SARS-CoV-2. (A) Bioactive peptides, their receptors and (B) their functions. For involved proteins, see Supplementary Figure S1. The KKS and RAS are connected by the action of the angiotensin-converting enzyme (ACE), which deactivates bradykinin (BK) and cleaves angiotensin (Ang) I to Ang II. Vasoactive BK is formed from kininogen by the action of kallikrein. The latter needs the Hageman factor to be cleaved from its precursor, and it also influences the RAS by catalyzing the cleavage of prorenin to renin, which, in turn, assists the formation of Ang I from angiotensinogen. The generation of Ang II ensures blood pressure homeostasis and is counter-balanced by ACE2, which cleaves Ang II. Carboxypeptidase N (CPN) degrades BK to des-Arg9-BK, which can be deactivated by ACE2. In the classical RAS, Ang II binds to its receptors AT1R and AT2R with opposite effects on, among other functions, blood pressure and inflammation. The main antagonist to the classical RAS is ACE2, which removes Ang II by cleavage to Ang (1–7); this peptide binds to the Mas receptor (MasR), thereby reducing blood pressure. BK acts via receptors B1 and B2. CPN cleaves BK and thus changes receptor specificity from B2R to B1R [7,8,9]. ACE inactivates BK, and ACE2 cleaves des-Arg9-BK. More processes involving several other enzymes such as neutral endopeptidase/neprylisin (NEP) have been described in addition to the main pathways. Positions where inhibitors (ACEIs/ARBs) act are marked. The figures were assembled based on information collected in refs. [5,6] and reviews [2,3,10,11,12]. AD—aspartate decarboxylase, APA—aminopeptidase A, APN—alanyl aminopeptidase N, CPA—carboxypeptidase A, MRGD—Mas-related G protein-coupled receptor member D, NO—nitric oxide, PEP—prolyl endopeptidase, PSNS—parasympathetic nervous system, ROS—reactive oxygen species, SNS—sympathetic nervous system, THOP1—thiocyanate oligopeptidase, VSMC—vascular smooth muscle cells.

Figure 1

The connection of the kallikrein–kinin system (KKS) and the renin–angiotensin system (RAS) with respect to intervention by SARS-CoV-2. (A) Bioactive peptides, their receptors and (B) their functions. For involved proteins, see Supplementary Figure S1. The KKS and RAS are connected by the action of the angiotensin-converting enzyme (ACE), which deactivates bradykinin (BK) and cleaves angiotensin (Ang) I to Ang II. Vasoactive BK is formed from kininogen by the action of kallikrein. The latter needs the Hageman factor to be cleaved from its precursor, and it also influences the RAS by catalyzing the cleavage of prorenin to renin, which, in turn, assists the formation of Ang I from angiotensinogen. The generation of Ang II ensures blood pressure homeostasis and is counter-balanced by ACE2, which cleaves Ang II. Carboxypeptidase N (CPN) degrades BK to des-Arg9-BK, which can be deactivated by ACE2. In the classical RAS, Ang II binds to its receptors AT1R and AT2R with opposite effects on, among other functions, blood pressure and inflammation. The main antagonist to the classical RAS is ACE2, which removes Ang II by cleavage to Ang (1–7); this peptide binds to the Mas receptor (MasR), thereby reducing blood pressure. BK acts via receptors B1 and B2. CPN cleaves BK and thus changes receptor specificity from B2R to B1R [7,8,9]. ACE inactivates BK, and ACE2 cleaves des-Arg9-BK. More processes involving several other enzymes such as neutral endopeptidase/neprylisin (NEP) have been described in addition to the main pathways. Positions where inhibitors (ACEIs/ARBs) act are marked. The figures were assembled based on information collected in refs. [5,6] and reviews [2,3,10,11,12]. AD—aspartate decarboxylase, APA—aminopeptidase A, APN—alanyl aminopeptidase N, CPA—carboxypeptidase A, MRGD—Mas-related G protein-coupled receptor member D, NO—nitric oxide, PEP—prolyl endopeptidase, PSNS—parasympathetic nervous system, ROS—reactive oxygen species, SNS—sympathetic nervous system, THOP1—thiocyanate oligopeptidase, VSMC—vascular smooth muscle cells.