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Cited by 111COVID-19 Clinical Research StudiesRenin-Angiotensin System StudiesSARS-CoV-2 and COVID-19 Research

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

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Rysz, Susanne, Al-Saadi, Jonathan, Sjöström, Anna, Farm, Maria, Campoccia Jalde, Francesca, Plattén, Michael, Eriksson, Helen, Klein, Margareta, Vargas-Paris, Roberto, Nyrén, Sven, Abdula, Goran, Ouellette, Russell, Granberg, Tobias, Jonsson Fagerlund, Malin, Lundberg, Johan·2021·Nature Communications
DOI 10.1038/s41467-021-22713-zPMC PMC8065208

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Abstract

Abstract SARS-CoV-2 enters the cell through the ACE2 receptor, which is considered one of the main inhibitors in the Renin-Angiotensin-Aldosterone System (RAAS).1​ ,2 The virus has been shown to downregulate the ACE2 receptor, leading to a subsequent increase in the vasopressoragentangiotensinII.3​ Evidently,criticalcoronavirusdisease2019(COVID-19)is thought to be due to a dysregulated immune response, causing a cytokine-release syndrome eventually leading to acute respiratory distress syndrome (ARDS).4​ ,5 ​However, several reports on clinical laboratory features and case-descriptions of critically ill patients with COVID-19 show discrepancies compared to typical ARDS. Here, we show that infusing swines with angiotensin II induces a pathophysiological syndrome closely resembling that of patients with RT-PCR-positive COVID-19. By using multimodal clinical imaging of patients, comparing laboratory data and translational histological features, we show that it is highly likely that an increase in RAAS is one, if not the main, pathogenic feature in critical COVID-19. Furthermore, it is plausible that this large animal model can be used to screen for potential new treatments for patients with severe COVID-19 and that MRI lung perfusion can be used to evaluate the outcome of potential treatments targeting the pathophysiological syndrome.

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Crossref · 10.1038/s41467-021-22713-z

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Figures

Fig. 1 Flowchart of the CTPA cohort and subsequent analyses. CT: computed tomography; CTPA: computed tomography pulmonary angiography; PA: pulmonary artery.
Fig. 1 Flowchart of the CTPA cohort and subsequent analyses. CT: computed tomography; CTPA: computed tomography pulmonary angiography; PA: pulmonary artery.CC BY · PubMed Central
Fig. 2 MRI of a patient with COVID-19. a Time-to-peak map of the patient’s lung. The color lookup table has been set to maximum blue for pulmonary artery peak and yellow for aortic peak or later. Note large yellow areas dominating the periphery of the lungs, signifying late or no arrival of contrast. b Reference coronal T2-weighted scan to identify infiltrates. Reviewed together, perfusion disturbances are apparent both within lung infiltrates and in the normal-appearing pulmonary parenchyma.
Fig. 2 MRI of a patient with COVID-19. a Time-to-peak map of the patient’s lung. The color lookup table has been set to maximum blue for pulmonary artery peak and yellow for aortic peak or later. Note large yellow areas dominating the periphery of the lungs, signifying late or no arrival of contrast. b Reference coronal T2-weighted scan to identify infiltrates. Reviewed together, perfusion disturbances are apparent both within lung infiltrates and in the normal-appearing pulmonary parenchyma.CC BY · PubMed Central
Fig. 3 Flowchart of preclinical experiments. ACE2: Angiotensin-converting enzyme 2; ANGII: Angiotensin II; RAAS: Renin-Angiotensin-Aldosterone System; DVT: Deep Venous Thrombosis; MRI: Magnetic Resonance Imaging.
Fig. 3 Flowchart of preclinical experiments. ACE2: Angiotensin-converting enzyme 2; ANGII: Angiotensin II; RAAS: Renin-Angiotensin-Aldosterone System; DVT: Deep Venous Thrombosis; MRI: Magnetic Resonance Imaging.CC BY · PubMed Central
Fig. 4 Physiological measurements by groups across time. a Mean arterial pressure. b Systolic pulmonary artery pressure. c Cardiac index. d Mixed venous saturation. In all graphs, red represents individuals in the model group, blue represents individuals in the control group and, green represents individuals in the treatment group. Source data are provided as source data file.
Fig. 4 Physiological measurements by groups across time. a Mean arterial pressure. b Systolic pulmonary artery pressure. c Cardiac index. d Mixed venous saturation. In all graphs, red represents individuals in the model group, blue represents individuals in the control group and, green represents individuals in the treatment group. Source data are provided as source data file.CC BY · PubMed Central
Fig. 5 Individual blood gas analysis in arterial blood across time. a Partial pressure of oxygen. b Blood oxygen saturation. c Partial pressure of carbon dioxide. Red diamonds represent model individuals, blue control individuals, and green treatment individuals. Source data are provided as source data file.
Fig. 5 Individual blood gas analysis in arterial blood across time. a Partial pressure of oxygen. b Blood oxygen saturation. c Partial pressure of carbon dioxide. Red diamonds represent model individuals, blue control individuals, and green treatment individuals. Source data are provided as source data file.CC BY · PubMed Central
Fig. 6 Swine MRI perfusion. a Time-to-peak map of a model swine lung that has received ACE2 inhibition by MLN-4760 and low dose ANGII with the color lookup table set to maximum blue for pulmonary artery peak and yellow for aortic peak or later. b Control swine that has been sedated and performed MRI lung perfusion at approximately the same sedation time as the swine in a. c Treatment swine that has been given oral angiotensin receptor blocker and low molecular weight heparin.
Fig. 6 Swine MRI perfusion. a Time-to-peak map of a model swine lung that has received ACE2 inhibition by MLN-4760 and low dose ANGII with the color lookup table set to maximum blue for pulmonary artery peak and yellow for aortic peak or later. b Control swine that has been sedated and performed MRI lung perfusion at approximately the same sedation time as the swine in a. c Treatment swine that has been given oral angiotensin receptor blocker and low molecular weight heparin.CC BY · PubMed Central
Fig. 7 Time-to-peak distribution in lungs of swine. a The distribution of peaks in every individual is plotted with the thinner lines and a solid line represents the mean peak distribution throughout the lungs. In all graphs, red represents the model group, blue represents the control group and, green represents the treatment group. The vertical black bar represents the aorta peak and the cutoff for functional ratio, calculated as the proportion of lung with delayed perfusion (peaking after the aorta). b Individual functional ratios represented by dots and a mean bar with standard deviation whiskers for each group of control (n = 4), model (n = 4), and treatment (n = 3). c The mean time-to-peak of the lungs with each individual as a scatter plot and mean and standard deviation as whiskers. Source data are provided as source data file.
Fig. 7 Time-to-peak distribution in lungs of swine. a The distribution of peaks in every individual is plotted with the thinner lines and a solid line represents the mean peak distribution throughout the lungs. In all graphs, red represents the model group, blue represents the control group and, green represents the treatment group. The vertical black bar represents the aorta peak and the cutoff for functional ratio, calculated as the proportion of lung with delayed perfusion (peaking after the aorta). b Individual functional ratios represented by dots and a mean bar with standard deviation whiskers for each group of control (n = 4), model (n = 4), and treatment (n = 3). c The mean time-to-peak of the lungs with each individual as a scatter plot and mean and standard deviation as whiskers. Source data are provided as source data file.CC BY · PubMed Central
Fig. 8 Macroscopic and histological postmortem examination. a Model lungs. Image of posterior aspect with discoloring. b Coronal cut through the posterior aspect of the model lung. c Control lungs. Image of posterior aspect. d Similar coronal cut of a control lung. e The dominating microscopic image in the model lungs was blood stasis in vessels of all sizes. This corresponded to areas with stasis perfusion as illustrated by a parametric max enhancement map from the same model animal (yellow is higher contrast enhancement). f High power magnification (x40) with fluids in the alveolar sacs and sloughing of pneumocytes into the alveolar space (marked by arrows), consistent with early diffuse alveolar damage (scale bar 100 µm). g Parametric relative contrast enhancement, with same color lookup table setting as in e, of control animal. h High power magnification showing a fluid collection in control lung (marked by arrow) in the alveolar sacs (scale bar 100 µm). i The macroscopic texture of the model lung was rubbery. Large areas of the model lungs were fully consolidated (scale bar 2.5 mm). j Fluids and cells in bronchi in a fully consolidated model lung (scale bar 100 µm). k In small areas in the most posterior aspects of the model lungs we could also identify fully consolidated lung (arrow, scale bar 2.5 mm). l Ventilated bronchi in fully consolidated control lungs (scale bar 100 µm). m Model kidney. n Histological sample from model kidney with narrowing of proximal tubule wall thickness and sloughing of epithelial cells (arrows), consistent with acute tubular necrosis (scale bar 100 µm). o Control kidney. p Control kidney without signs of acute tubular necrosis (scale bar 100 µm). q Model liver without histological damage (scale bar 250 µm). r Model small bowel (scale bar 500 µm). s Control liver (scale bar 250 µm). t Control small bowel (scale bar 500 µm).
Fig. 8 Macroscopic and histological postmortem examination. a Model lungs. Image of posterior aspect with discoloring. b Coronal cut through the posterior aspect of the model lung. c Control lungs. Image of posterior aspect. d Similar coronal cut of a control lung. e The dominating microscopic image in the model lungs was blood stasis in vessels of all sizes. This corresponded to areas with stasis perfusion as illustrated by a parametric max enhancement map from the same model animal (yellow is higher contrast enhancement). f High power magnification (x40) with fluids in the alveolar sacs and sloughing of pneumocytes into the alveolar space (marked by arrows), consistent with early diffuse alveolar damage (scale bar 100 µm). g Parametric relative contrast enhancement, with same color lookup table setting as in e, of control animal. h High power magnification showing a fluid collection in control lung (marked by arrow) in the alveolar sacs (scale bar 100 µm). i The macroscopic texture of the model lung was rubbery. Large areas of the model lungs were fully consolidated (scale bar 2.5 mm). j Fluids and cells in bronchi in a fully consolidated model lung (scale bar 100 µm). k In small areas in the most posterior aspects of the model lungs we could also identify fully consolidated lung (arrow, scale bar 2.5 mm). l Ventilated bronchi in fully consolidated control lungs (scale bar 100 µm). m Model kidney. n Histological sample from model kidney with narrowing of proximal tubule wall thickness and sloughing of epithelial cells (arrows), consistent with acute tubular necrosis (scale bar 100 µm). o Control kidney. p Control kidney without signs of acute tubular necrosis (scale bar 100 µm). q Model liver without histological damage (scale bar 250 µm). r Model small bowel (scale bar 500 µm). s Control liver (scale bar 250 µm). t Control small bowel (scale bar 500 µm).CC BY · PubMed Central

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Authors
Rysz, S., Al-Saadi, J., Sjöström, A., Farm, M., Campoccia Jalde, F., Plattén, M., Eriksson, H., Klein, M., Vargas-Paris, R., Nyrén, S., Abdula, G., Ouellette, R., Granberg, T., Jonsson Fagerlund, M., & Lundberg, J.
Affiliations
Karolinska University Hospital (SE)
Corresponding author
Lundberg, Johan
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-04-23
Volume
12
Issue
1
Pages
2417-2417
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-22713-z
PMC
PMC8065208
OpenAlex
W3152933878
Cited by
111
References
57
Citations by year
2026: 9 · 2025: 9 · 2024: 17 · 2023: 26 · 2022: 30 · 2021: 17
FWCI
7.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Stockholm Region Clinical Post doc and ALF
  • Stockholm Region Clinical Post Doc, Tedde Jeansson Sr and, MedTechLabs.
Topics
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
COVID-19 pandemic, SARS-CoV-2, renin-angiotensin-aldosterone system, ACE2, angiotensin II, pulmonary embolism, pulmonary artery pressure, pulmonary blood flow, coagulation, acute tubular necrosis, diffuse alveolar damage, angiotensin receptor blockers, low molecular weight heparin, porcine model, pathophysiology
MeSH terms
Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Angiotensin II, Animals, Female, Humans, Lung, Magnetic Resonance Imaging, Protein Binding, Renin-Angiotensin System, Retrospective Studies, Swine, Virus Internalization, Angiotensin Receptor Antagonists, Spike Glycoprotein, Coronavirus

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