Preprint Communication Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 17 May 2023 / Approved: 18 May 2023 / Online: 18 May 2023 (08:13:10 CEST)

A peer-reviewed article of this Preprint also exists.

König, S.; Vollenberg, R.; Tepasse, P.-R. The Renin–Angiotensin System in COVID-19: Can Long COVID Be Predicted? Life 2023, 13, 1462. König, S.; Vollenberg, R.; Tepasse, P.-R. The Renin–Angiotensin System in COVID-19: Can Long COVID Be Predicted? Life 2023, 13, 1462.


(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 counterbalanced 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, thus, currently directed towards the components of these systems. In an earlier study, we noticed significantly reduced carboxypeptidase N (CPN, KKS member) activity and partially excessive angiotensin-converting enzyme (ACE, RAS member) activity in the sera of both hospitalized (HoP) COVID-19 patients and a sub-group of covalescent patients, while in the majority of the probands recovering from the disease these values had returned to normal. The data had been obtained using bradykinin (BK) as a reporter peptide, which is a target of both CPN and ACE, and they were supplemented by serum proteomics of the same patient cohort. We hypothesized that the data could be indicative of Long COVID, which had not been fully appreciated at the time of our study.; (2) Methods: The data were re-evaluated in the light of Long COVID. The recent literature on the RAS in COVID-19, antihypertensiva, and Long COVID was briefly reviewed.; (3) Results: While the levels of the BK serum degradation products should return to normal concentrations during convalescence, this was not true for some patients. This could be due to persisting liver problems, because CPN is synthesized there, but also to a dysregulated RAS. This was not reflected in the levels of selected RAS/KKS serum proteins like angiotensinogen (AGT), although AGT correlated with disease severity in HoP. However, standard tests in routine patient care in Long COVID often come back normal, and it may be that BK degradation is specific in some pathophysiologies. Moreover, the HoP group was sub-divided based on the serum protein profiles and COVID-19 severity.; (4) Conclusions: We point out two insights: 1) Sensitive technology such as omics methods might provide unexpected significant differences within the pre-defined patient groups of a clinical study. Those can only be explored, if the cohorts are large enough and properly matched with respect to the parameters known beforehand (e.g., age, gender, co-morbidities). 2) Results of the BK-reporter serum protease activity assay could be indicative of persisting liver problems and/or potentially of Long COVID. Clinical studies are required to test this hypothesis.


Mass spectrometry; RAS; ACE; ACE2; CPN; bradykinin; hypertension; cardiovascular disease; antihypertensiva; ACE inhibitors; angiotensin receptor blockers; bradykinin; neuropeptide re-porter assay


Biology and Life Sciences, Life Sciences

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