The Renin-Angiotensin-Aldosterone System in Coronavirus-19 Disease Pathogenesis: Extracting the Devil in the Details.

Abstract

Coronavirus 2019 disease (COVID-19) was first recognised as an acute febrile respiratory syndrome. Soon, it was realised that acute kidney injury, myocarditis, cytokine activation and prothrombotic disseminated intravascular coagulation are also part of the syndrome complex. Currently, it is being recognised as causing microangiopathy as well as thrombo-embolic complications. The SARS-CoV-2 coronavirus enters cells via the ACE2 (Angiotensin converting enzyme-2) receptor and leads to its downregulation. The loss of ACE2 is postulated to cause activation of the Renin Angiotensin Aldosterone System (RAAS) that contributes to cardiac and renal pathology. Supporting the hypothesis that ACE2 loss can explain the entire pathology, we have reviewed the available literature to determine mechanistic associations between RAAS and the various manifestations of COVID-19. ACE2 dependent protective pathways include the Angiotensin(1-7)/Mas receptor and Alamandine/MrgD receptor pathways. These are anti-hypertensive, anti-inflammatory, and anti-thrombotic. Loss of ACE2 leads to Angiotensin II and aldosterone accumulation that causes thrombosis via release of Plasminogen Activator Inhibitor-1(PAI-1). Altered ACE1/ACE2 balance can activate immune cells and cause polarization of macrophages into M2-inflammatory phenotype. Animal models of various viral pneumonias have previously shown that ACE2 loss is associated with severe lung injury. Angiotensin II and aldosterone are known causes of cardiomyopathy and also potentiate acute kidney injury. There is some emerging evidence that inhibitors of canonical RAAS such as ACE inhibitors, Angiotensin receptor blockers, and statins may have mortality benefit in COVID-19. Heparin inhibits both thrombosis and RAAS, and has definite mortality benefit at least in a subset of COVID-19 patients. Activated Protein C may be helpful for the microangiopathic thrombosis. We strongly advocate that treatment strategies for COVID-19 should include synergistic targeting of the RAAS and coagulation systems.