A low aldosterone/renin ratio and high soluble ACE2 associate with COVID-19 severity

Abstract

Background: The severity of COVID-19 after SARS-CoV-2 infection is unpredictable. Angiotensin-converting enzyme-2 (ACE2) is the receptor responsible for coronavirus binding, while subsequent cell entry relies on priming by the serine protease TMPRSS2 (transmembrane protease, serine 2). Although renin-angiotensin-aldosterone-system (RAAS) blockers have been suggested to upregulate ACE2, their use in COVID-19 patients is now considered well tolerated. The aim of our study was to investigate parameters that determine COVID-19 severity, focusing on RAAS-components and variation in the genes encoding for ACE2 and TMPRSS2. Methods: Adult patients hospitalized due to SARS-CoV-2 infection between May 2020 and October 2020 in the Haga Teaching Hospital were included, and soluble ACE2 (sACE2), renin, aldosterone (in heparin plasma) and polymorphisms in the ACE2 and TMPRSS2 genes (in DNA obtained from EDTA blood) were determined. Measurements and main results: Out of the 188 patients who were included, 60 were defined as severe COVID-19 (ICU and/or death). These patients more often used antidiabetic drugs, were older, had higher renin and sACE2 levels, lower aldosterone levels and a lower aldosterone/renin ratio. In addition, they displayed the TMPRSS2-rs2070788 AA genotype less frequently. No ACE2 polymorphism-related differences were observed. Multivariate regression analysis revealed independent significance for age, sACE2, the aldosterone/renin ratio, and the TMPRSS2 rs2070788 non-AA genotype as predictors of COVID-19 severity, together yielding a C-index of 0.79. Findings were independent of the use of RAAS blockers. Conclusion: High sACE2, a low aldosterone/renin ratio and having the TMPRSS2 rs2070788 non-AA genotype are novel independent determinants that may help to predict COVID-19 disease severity. Trial registration: retrospectively registered.

Mineralocorticoid receptor and glucocorticoid receptor work alone and together in cell-type-specific manner: Implications for resilience prediction and targeted therapy

“…While this preliminary observation supports a pro-inflammatory mineralocorticoid action in the course of COVID-19, in the later stage when the cytokine storm arises, the potent anti-inflammatory synthetic glucocorticoid dexamethasone appeared a life-saver, which is in line with the role of glucocorticoids in limiting overshoot of immune defense ( Horby et al, 2020 ). Collectively, these findings illustrate the pendulum hypothesis, if further validated for mineralocorticoids ( Akin et al, 2022 ). Alt-text: Box 1

In rodents, there is a stress hyporesponsive period (SHRP) in which responses to mild and moderate stressors do not increase glucocorticoid secretion ( Levine et al, 1991 ), and pups learn to remain with the dam irrespective the aversiveness of the environment ( Moriceau and Sullivan, 2006 ).

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“…While this preliminary observation supports a pro-inflammatory mineralocorticoid action in the course of COVID-19, in the later stage when the cytokine storm arises, the potent anti-inflammatory synthetic glucocorticoid dexamethasone appeared a life-saver, which is in line with the role of glucocorticoids in limiting overshoot of immune defense ( Horby et al, 2020 ). Collectively, these findings illustrate the pendulum hypothesis, if further validated for mineralocorticoids ( Akin et al, 2022 ).…”

The association of ACE1, ACE2, TMPRSS2, IFITM3 and VDR polymorphisms with COVID-19 severity: a systematic review and meta-analysis

“…Basic characteristics of the remaining 29 studies (Abdollahzadeh et al, 2021[ 1 ]; Aladag et al, 2021[ 4 ]; Al-Anouti et al, 2021[ 5 ]; Alghamdi et al, 2021[ 6 ]; Akbari et al, 2022[ 2 ]; Akin et al, 2022[ 3 ]; Apaydin et al, 2022[ 7 ]; Cafiero et al, 2021[ 10 ]; Karakaş Çelik et al, 2021[ 26 ]; Cuesta-Llavona et al, 2021[ 13 ]; Gómez et al, 2020[ 20 ]; Gómez et al, 2021[ 19 ]; Gunal et al, 2021[ 21 ]; Hubacek et al, 2021[ 23 ]; Íñiguez et al, 2021[ 24 ]; Kotur et al, 2021[ 27 ]; Kouhpayeh et al, 2021[ 28 ]; Mir et al, 2021[ 33 ]; Möhlendick et al, 2021[ 34 ]; Monticelli et al, 2021[ 35 ]; Novelli et al, 2020[ 36 ]; Peralta et al, 2021[ 39 ]; Ravikanth et al, 2021[ 43 ]; Saad et al, 2021[ 45 ]; Schönfelder et al, 2021[ 49 ][ 48 ]; Verma et al, 2021[ 53 ]; Wang et al, 2022[ 55 ]; Wulandari et al, 2021[ 57 ]; Zhang et al, 2020[ 59 ]), with a total number of 8247 SARS-CoV-2-positive participants, included in qualitative data synthesis, are given in Table 1 (Tab. 1) (References in Table 1: Abdollahzadeh et al, 2021[ 1 ]; Akbari et al, 2022[ 2 ]; Akin et al, 2022[ 3 ]; Aladag et al, 2021[ 4 ]; Al-Anouti et al, 2021[ 5 ]; Alghamdi et al, 2021[ 6 ]; Apaydin et al, 2022[ 7 ]; Cafiero et al, 2021[ 10 ]; Cuesta-Llavona et al, 2021[ 13 ]; Gómez et al , 2020[ 20 ], 2021[ 19 ]; Gunal et al, 2021[ 21 ]; Hubacek et al, 2021[ 23 ]; Íñiguez et al, 2021[ 24 ]; Karakaş Çelik et al, 2021[ 26 ]; Kotur et al, 2021[ 27 ]; Kouhpayeh et al, 2021;[ 28 ] Mir et al, 2021[ 33 ]; Möhlendick et al, 2021[ 34 ]; Monticelli et al, 2021[ …”

Commentary: Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells

“…On the one hand, it may activate the plasma ACE2/ Ang1-7/alamandine pathway, and more importantly it seems to represent a decoy for circulating SARS-CoV-2 virus, preventing its interactions with mACE2 and cellular internalization (Batlle et al, 2020); both actions are potentially protective. On the other hand, increased sACE2 could indicate accelerated mACE2 splitting, attenuating activation of the tissue ACE2/Ang1-7/ MasR pathway, and increased sACE2 has been suggested as a potential marker of compromised prognosis in cardiovascular pathologies (Sama et al, 2020;Oudit and Pfeffer, 2020) or in patients with severe COVID-19 (Akin et al, 2021).…”