COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin-aldosterone system

Rysz, Susanne; Al-Saadi, Jonathan; Sjöström, Anna; Farm, Maria; Jalde, Francesca Campoccia; Plattén, Michael; Eriksson, Helén; Klein, Margareta; Vargas-Paris, Roberto; Nyrén, Sven; Abdula, Goran; Ouellette, Russell; Granberg, Tobias; Fagerlund, Malin Jonsson; Lundberg, Johan

doi:10.1038/s41467-021-22713-z

Cited by 92 publications

(101 citation statements)

References 37 publications

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“…In a retrospective US large cohort, metformin was significantly linked to reduced death in women ( 51 ). A small Chinese cohort also examined metformin effects ( 56 ). Metformin has hypothetically been suggested for the treatment of patients with COVID-19 at risk of developing severe illness ( 60 ).…”

Section: Discussionmentioning

confidence: 99%

Preliminary Evidence for IL-10-Induced ACE2 mRNA Expression in Lung-Derived and Endothelial Cells: Implications for SARS-Cov-2 ARDS Pathogenesis

et al. 2021

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Angiotensin-converting enzyme 2 (ACE2) is a receptor for the spike protein of SARS-COV-2 that allows viral binding and entry and is expressed on the surface of several pulmonary and non-pulmonary cell types, with induction of a “cytokine storm” upon binding. Other cell types present the receptor and can be infected, including cardiac, renal, intestinal, and endothelial cells. High ACE2 levels protect from inflammation. Despite the relevance of ACE2 levels in COVID-19 pathogenesis, experimental studies to comprehensively address the question of ACE2 regulations are still limited. A relevant observation from the clinic is that, besides the pro-inflammatory cytokines, such as IL-6 and IL-1β, the anti-inflammatory cytokine IL-10 is also elevated in worse prognosis patients. This could represent somehow a “danger signal”, an alarmin from the host organism, given the immuno-regulatory properties of the cytokine. Here, we investigated whether IL-10 could increase ACE2 expression in the lung-derived Calu-3 cell line. We provided preliminary evidence of ACE2 mRNA increase in cells of lung origin in vitro, following IL-10 treatment. Endothelial cell infection by SARS-COV-2 is associated with vasculitis, thromboembolism, and disseminated intravascular coagulation. We confirmed ACE2 expression enhancement by IL-10 treatment also on endothelial cells. The sartans (olmesartan and losartan) showed non-statistically significant ACE2 modulation in Calu-3 and endothelial cells, as compared to untreated control cells. We observed that the antidiabetic biguanide metformin, a putative anti-inflammatory agent, also upregulates ACE2 expression in Calu-3 and endothelial cells. We hypothesized that IL-10 could be a danger signal, and its elevation could possibly represent a feedback mechanism fighting inflammation. Although further confirmatory studies are required, inducing IL-10 upregulation could be clinically relevant in COVID-19-associated acute respiratory distress syndrome (ARDS) and vasculitis, by reinforcing ACE2 levels.

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Section: Discussionmentioning

confidence: 99%

Preliminary Evidence for IL-10-Induced ACE2 mRNA Expression in Lung-Derived and Endothelial Cells: Implications for SARS-Cov-2 ARDS Pathogenesis

et al. 2021

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“…The spectrum of COVID-19 cases varies from asymptomatic to severe and fatal. In general, the clinical deterioration of patients infected with SARS-CoV-2 is thought to be the result of cytokine storms, and/or the renin-angiotensin-aldosterone system imbalance ( Abdel-Moneim et al, 2021 ; Liu et al, 2020 ; Rysz et al, 2021 ). In Egypt, the treatment protocol for COVID-19 patients includes the use of the macrolide antimicrobial azithromycin (AZM), which has been suggested to have anti-inflammatory properties through inhibiting the production of pro-inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of FOXP3 is associated with severity of hypoxia and poor outcomes in COVID-19 patients

et al. 2021

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The levels of messenger RNA (mRNA) transcription of FOXP3, IFN-γ, TNF, IL-6 and COX-2 from both COVID-19 infected and control subjects were evaluated using SYBR TM green real-time polymerase chain reaction (RT-PCR). Severe/critical cases showed significantly lower lymphocyte counts and higher neutrophil counts than the mild or moderate cases. There were significantly lower levels of mRNA expressions of IFN-γ, TNFα and FOXP3 in COVID-19 patients than in the control group. On the other hand, IL-6 and COX-2 expressions were significantly higher in patients suffering from severe disease. FOXP3 expressions were correlated with the severities of hypoxia and were excellent in predicting the disease severity. This was followed by the IL-6, COX-2 and TNFα expressions. FOXP3 expression was the only biomarker to show a significant correlation with patient mortality. It was concluded that SARS-CoV-2 infection is associated with the downregulation of FOXP3 and upregulations of IL-6 and COX-2 .

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“…The imbalance between ACE2/angiotensin axis and RAS have also been implicated in multi-organ injury associated with COVID-19 ( 108 ). RAS imbalance in a swine model induced a pathophysiological phenotype with systemic effects, comprising of diffused alveolar damage, disturbed lung perfusion, increased coagulation, reduced blood oxygenation, increased pulmonary arterial pressure and acute tubular necrosis, that shared similarities with clinical COVID-19 presentation ( 109 ). The RAS imbalance in the acute COVID-19 phase may cause substantial end-organ damage in lung, heart, kidney and small intestine amongst others, paving way for long-term health outcomes in these patients.…”

Section: Potential Immunopathological Mechanisms Underlying Post-acute Sequelae Of Covid-19mentioning

confidence: 97%

Unraveling the Mystery Surrounding Post-Acute Sequelae of COVID-19

et al. 2021

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More than one year since its emergence, corona virus disease 2019 (COVID-19) is still looming large with a paucity of treatment options. To add to this burden, a sizeable subset of patients who have recovered from acute COVID-19 infection have reported lingering symptoms, leading to significant disability and impairment of their daily life activities. These patients are considered to suffer from what has been termed as “chronic” or “long” COVID-19 or a form of post-acute sequelae of COVID-19, and patients experiencing this syndrome have been termed COVID-19 long-haulers. Despite recovery from infection, the persistence of atypical chronic symptoms, including extreme fatigue, shortness of breath, joint pains, brain fogs, anxiety and depression, that could last for months implies an underlying disease pathology that persist beyond the acute presentation of the disease. As opposed to the direct effects of the virus itself, the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is believed to be largely responsible for the appearance of these lasting symptoms, possibly through facilitating an ongoing inflammatory process. In this review, we hypothesize potential immunological mechanisms underlying these persistent and prolonged effects, and describe the multi-organ long-term manifestations of COVID-19.

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COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin-aldosterone system

Cited by 92 publications

References 37 publications

Preliminary Evidence for IL-10-Induced ACE2 mRNA Expression in Lung-Derived and Endothelial Cells: Implications for SARS-Cov-2 ARDS Pathogenesis

Preliminary Evidence for IL-10-Induced ACE2 mRNA Expression in Lung-Derived and Endothelial Cells: Implications for SARS-Cov-2 ARDS Pathogenesis

Upregulation of FOXP3 is associated with severity of hypoxia and poor outcomes in COVID-19 patients

Unraveling the Mystery Surrounding Post-Acute Sequelae of COVID-19

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