Abstract

The Renin-Angiotensin System (RAS) is a critical regulator of cardiovascular and fluid homeostasis, but its dysregulation has emerged as a central factor in the pathogenesis of severe COVID-19. The RAS is functionally divided into two main branches: the classical Angiotensin-Converting Enzyme (ACE)/Angiotensin II (Ang II)/Angiotensin II type 1 receptor (AT1R) axis, which is largely pro-inflammatory and pro-fibrotic, and the protective ACE2/Angiotensin-(1-7)/Mas receptor axis. The SARS-CoV-2 virus utilizes the ACE2 enzyme as its primary entry receptor on host cells, leading to the downregulation and functional depletion of membrane-bound ACE2. This depletion shifts the delicate balance of the RAS toward the detrimental ACE/Ang II/AT1R axis, resulting in excessive Ang II accumulation. This imbalance is hypothesized to drive the acute respiratory distress syndrome (ARDS), endothelial dysfunction, and cytokine storm characteristic of severe COVID-19. This study investigates the hypothesis that maintaining or restoring the balance between these two RAS branches, particularly by bolstering the protective ACE2/Ang-(1-7) axis, can mitigate the severe inflammatory and thrombotic consequences of SARS-CoV-2 infection. The findings suggest that therapeutic strategies aimed at modulating RAS balance, such as the use of AT1R blockers or Ang-(1-7) analogs, may offer a protective mechanism against the progression to critical illness in COVID-19 patients.