Impaired Breakdown of Bradykinin and Its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection

A growing body of clinical evidence shows that vascular leakage leads to pulmonary edema in coronavirus disease 2019 (COVID-19) patients. Coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) use membrane ectopeptidases to invade cells, most notably dipeptidyl peptidase 4 (DPP4; https://www.uniprot.org/uniprot/P27487), aminopeptidase N (APN; https://www.uniprot.org/uniprot/P15144), and angiotensin-converting enzyme 2 (ACE2; https://www.uniprot.org/uniprot/Q9BYF1).[1] It is important to distinguish this latter protein from ACE, which is the main target for conventional blood pressure lowering drugs: ACE inhibitors do not inhibit ACE2.[2] As a result of virus entry, these membrane ectopeptidases are internalized and their activity becomes downregulated. The common denominator between these membrane ectopeptidases is their enzyme specificity: they degrade peptide hormones, for instance, angiotensin II. For SARS-CoV-2 (as well as SARS-CoV), ACE2 is the predominant target for cellular uptake in vivo.[3] It is present on lung alveolar epithelial cells, enterocytes of the small intestine, endothelial cells, and arterial smooth muscle cells.[4] In an acid aspiration lung injury mouse model, ACE2 knockout (KO) worsened the resulting edema.[5] This was accompanied by increased angiotensin II levels[6] and was prevented by angiotensin II receptor KO, leading to the conclusion that the lack of ACE2-mediated angiotensin II degradation was responsible for the observed increase pulmonary vascular permeability. The same observations were made when downregulating ACE2 with the spike protein of the SARS CoV prior to acid aspiration.[6] Yet, the authors did not measure renin in these studies. This is crucial since normally angiotensin II rises result in rapid renin suppression,[7] thereby normalizing its levels. Moreover, ACE2 is just one of many angiotensin-degrading enzymes (angiotensinases). In full accordance with this concept, Gurley et al did not find increased angiotensin II levels after ACE2 KO.[8] Hence, whether the ACE2 KO dependent permeability changes are entirely due to ACE2-mediated angiotensin II degradation remains uncertain. ACE2 has multiple other substrates. Among these are the kinins, which are also degraded by DPP4.[9] We and others believe that this deserves attention, as it offers an alternative view, and forms a basis on which novel therapeutic opportunities might be proposed.[10]

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