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ACE2, ACE, DPPIV, PREP and CAT L enzymatic activities in COVID-19: imbalance of ACE2/ACE ratio and potential RAAS dysregulation in severe cases

  • Original Research Paper
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Abstract

Objective and design

Circulating enzymatic activity and RAAS regulation in severe cases of COVID-19 remains unclear, therefore we measured the serum activity of several proteases as potential targets to control the SARS-CoV-2 infection.

Material or subjects

152 patients with COVID-19-like symptoms were grouped according to the severity of symptoms (COVID-19 negative, mild, moderate and severe).

Methods

Serum samples of COVID-19 patients and controls were subjected to biochemical analysis and enzymatic assays of ACE2, ACE, DPPIV, PREP and CAT L. One-way ANOVA and multivariate logistic regression analysis were used. Statistical significance was accepted at p < 0.05.

Results

We detected a positive correlation among comorbidities, higher C-reactive protein (CRP) and D-dimer levels with disease severity. Enzymatic assays revealed an increase in serum ACE2 and CAT L activities in severe COVID-19 patients, while ACE, DPPIV and PREP activities were significantly reduced. Notably, analysis of ACE2/ACE activity ratio suggests a possible imbalance of ANG II/ANG(1-7) ratio, in a positive association with the disease severity.

Conclusion

Our findings reveal a correlation between proteases activity and the severity of COVID-19. These enzymes together contribute to the activation of pro-inflammatory pathways, trigger a systemic activation of inflammatory mediators, leading to a RAAS dysregulation and generating a significant damage in several organs, contributing to poor outcomes of severe cases.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding authors on reasonable request.

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Funding

This work was supported by grants from FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo—2014/27198-8, 2019/05266-5, 2019/01487-7) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico—423165/2021-6).

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  1. Raquel Leão Neves and Jéssica Branquinho contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Biophysics, Center for Research and Molecular Diagnostic of Genetic Diseases, Federal University of São Paulo, São Paulo, Brazil

    Raquel Leão Neves, Jéssica Branquinho, Júlia Galanakis Arata, Clarissa Azevedo Bittencourt, Caio Perez Gomes & João Bosco Pesquero

  2. Division of Nephrology, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil

    Michelle Riguetti, Gustavo Ferreira da Mata, Danilo Euclides Fernandes & Gianna Mastroianni Kirsztajn

  3. Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil

    Marcelo Yudi Icimoto

Authors
  1. Raquel Leão Neves
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  2. Jéssica Branquinho
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  3. Júlia Galanakis Arata
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  4. Clarissa Azevedo Bittencourt
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  11. João Bosco Pesquero
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Contributions

Conceptualization: JBP; methodology: RLN, JB, MR, GFM, DEF, JBP; formal analysis and investigation: RLN, JB, JGA, CAB, CPG, MYI; writing—original draft preparation: RLN, JB, MYI, GMK, JBP; writing—review and editing: RLN, JB, MYI, JBP; funding acquisition: MYI, GMK, JBP; resources: MYI, GMK; supervision: JBP.

Corresponding authors

Correspondence to Marcelo Yudi Icimoto, Gianna Mastroianni Kirsztajn or João Bosco Pesquero.

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Conflict of interest

The authors declare no conflict of interests.

Ethics approval

All procedures were conducted in accordance of the principles of Helsinki Declaration. Approval was granted by the Ethics Committee of the Federal University of São Paulo (CAAE 31929120.0.0000.5505). The patients provided their written informed consent to participate in this study and for the publication of any potentially data included in this article.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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Responsible Editor: Anatolii Kubyshkin.

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Neves, R.L., Branquinho, J., Arata, J.G. et al. ACE2, ACE, DPPIV, PREP and CAT L enzymatic activities in COVID-19: imbalance of ACE2/ACE ratio and potential RAAS dysregulation in severe cases. Inflamm. Res. 72, 1719–1731 (2023). https://doi.org/10.1007/s00011-023-01775-3

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