Figure 2.

Overactivation of the renin-angiotensin system (RAS) is a consequence of SARS-CoV-2 infection. Binding S protein to the angiotensin-converting enzyme 2 (ACE2) leads to receptor internalization and downregulation and causes upregulation of AngII. AngII binds to AT1R and activates the NFĸB pathway, causing the release of pro-inflammatory cytokines and inducing oxidative stress. Vitamin D3-VDR-RXR complex increases ACE2 and ACE2 augments the generation of angiotensin 1–7 (Ang (1–7)) by metabolizing Ang II. The Mas receptor (MasR) activated by Ang (1–7) induces beneficial actions such as anti-inflammation, anti-proliferation, anti-fibrotic, anti-apoptotic, and vasodilation. Vitamin D3 (VitD3) is also a poly(ADP-ribose) polymerase (PARP) inhibitor. VitD3 increases extracellular Ca²⁺ and results in the activation of transient receptor potential channels, melastatin 2 (TRPM2), and parthanatos.