Fig. 2
From: Does activation of the protective Renin-Angiotensin System have therapeutic potential in COVID-19?
Anti-inflammatory and anti-fibrotic pathways mediated by activated AT2R and/or MasR. The AT2R and MasR are expressed in the cell as monomers, homodimers and AT2R-MasR heterodimers (Leonhardt et al. 2017) and their downstream pathways are largely similar, making it often impossible to distinguish between them. During infection the AT1R becomes activated initiating inflammatory processes via NFκB and MAPK. Prolonged activation of AT1R may initiate pro-fibrotic processes with TGFβ as a key molecule. Agonist-mediated stimulation of AT2R or MasR inhibits activation of NFκB and MAPK resulting in anti-inflammation. For the anti-fibrotic action the inhibition of receptor tyrosine kinase activity by dephosphorylation on the one hand, and activation of cGMP on the other hand, plays a crucial role. In addition, heterodimerization between AT1R and AT2R or MasR inhibits detrimental effects mediated by AT1R. Blue lines: pro-fibrotic pathways; red lines: pro-inflammatory pathways; green lines: anti-inflammatory or anti-fibrotic pathways. AT2R / MasR: angiotensin II type 2 receptor or Mas receptor or AT2R-MasR heterodimers; TGFBR2: transforming growth factor beta receptor II; AT1R: angiotensin II type 1 receptor; RTKs: receptor tyrosine kinases; Akt: protein kinase B; PTP: protein tyrosine phosphatase; PSP: protein serine/threonine phosphatase; eNOS: nitric oxide synthase 3; NO: nitric oxide; cGMP: cyclic guanosine monophosphate; MMP9: matrix metallopeptidase 9; TGFβ: transforming growth factor beta; PDGF: platelet-derived growth factor; FGF: fibroblast growth factor; CTGF: connective tissue growth factor; VEGF: vascular endothelial growth factor; ECM: extracellular matrix; ERK: extracellular signal-regulated kinases; MAPK: mitogen-activated protein kinase; NOX: NADPH oxidase; ROS: reactive oxygen species; NFκB: nuclear factor kappa B; Gαi: G protein alpha i subunit; ATIP: AT2R-interacting proteins/microtubule-associated scaffold proteins; PP2A: protein phosphatase 2A; SHP-1: Src homology region 2 domain-containing phosphatase-1; MKP-1: MAPK Phosphatase 1. The pathways are based on: Unger et al. 2015; Sumners et al. 2019; Zhang et al. 2014; Leonhardt et al. 2017; Chappell and Al Zayadneh 2017