Figure 8.
Schematic representing the TGF-β1, ET-1 and Ang II networking on myofibroblast differentiation. In adult HCFs, Ang II stimulation of AT1Rs lead to an upregulation of TGF-β1 and ET-1 and activation of their effectors through the AT1R/Gαq axis. The activated AT1Rs transduce the signal through TGF-β1 cascade, which in turn upregulates ET-1 through the Smad-dependent and ERK1/2-dependent pathways. The elevated ET-1 then binds to and activates ETARs, leading to increases in collagen I and α-SMA synthesis and stress fiber formation. Interestingly, antagonism of AT1Rs and dual blockade of TGF-β1 receptors and ETRs exhibit antifibrotic effects by prevention and restoration of myofibroblast differentiation induced by Ang II. α-SMA: α-smooth muscle actin; Ang II: angiotensin II; AT1R: angiotensin II receptor type 1; ARB: angiotensin II receptor blocker; ET-1: Endothelin-1; ERAs: endothelin receptor antagonists; TβR I/II: TGF-β receptor type I and II.