New Horizons: Does Mineralocorticoid Receptor Activation by Cortisol Cause ATP Release and COVID-19 Complications?

J Clin Endocrinol Metab. 2021 Mar 8;106(3):622-635. doi: 10.1210/clinem/dgaa874.


This paper attempts to explain how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes the complications that make coronavirus disease 2019 (COVID-19) a serious disease in specific patient subgroups. It suggests that cortisol-associated activation of the mineralocorticoid receptor (MR) in epithelial and endothelial cells infected with the virus stimulates the release of adenosine 5'-triphosphate (ATP), which then acts back on purinergic receptors. In the lung this could produce the nonproductive cough via purinergic P2X3 receptors on vagal afferent nerves. In endothelial cells it could stimulate exocytosis of Weibel-Palade bodies (WPBs) that contain angiopoietin-2, which is important in the pathogenesis of acute respiratory distress syndrome (ARDS) by increasing capillary permeability and von Willebrand factor (VWF), which mediates platelet adhesion to the endothelium and hence clotting. Angiopoietin-2 and VWF levels both are markedly elevated in COVID-19-associated ARDS. This paper offers an explanation for the sex differences in SARS-CoV-2 complications and also for why these are strongly associated with age, race, diabetes, and body mass index. It also explains why individuals with blood group A have a higher risk of severe infection than those with blood group O. Dexamethasone has been shown to be of benefit in coronavirus ARDS patients and has been thought to act as an anti-inflammatory drug. This paper suggests that a major part of its effect may be due to suppression of cortisol secretion. There is an urgent need to trial the combination of dexamethasone and an MR antagonist such as spironolactone to more effectively block the MR and hence the exocytosis of WPBs.

Keywords: COVID-19 complications; mineralocorticoid receptor; spironolactone and dexamethasone.

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Angiotensin-Converting Enzyme 2 / physiology
  • Blood Coagulation Disorders / etiology
  • Blood Coagulation Disorders / metabolism
  • Blood Coagulation Disorders / virology
  • COVID-19 / complications*
  • COVID-19 / metabolism
  • COVID-19 / pathology
  • COVID-19 Drug Treatment
  • Dexamethasone / therapeutic use
  • Eplerenone / therapeutic use
  • Humans
  • Hydrocortisone / adverse effects
  • Hydrocortisone / metabolism
  • Hydrocortisone / pharmacology*
  • Mineralocorticoid Receptor Antagonists / therapeutic use
  • Models, Biological
  • Paracrine Communication / drug effects
  • Receptors, Mineralocorticoid / agonists*
  • Receptors, Mineralocorticoid / metabolism
  • Receptors, Purinergic / physiology
  • Respiratory Distress Syndrome / complications
  • Respiratory Distress Syndrome / metabolism
  • Respiratory Distress Syndrome / virology
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / pathogenicity
  • Severity of Illness Index
  • Spironolactone / therapeutic use


  • Mineralocorticoid Receptor Antagonists
  • Receptors, Mineralocorticoid
  • Receptors, Purinergic
  • Spironolactone
  • Eplerenone
  • Dexamethasone
  • Adenosine Triphosphate
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Hydrocortisone