Figure 5. Common signaling pathways activated by ANG II, ET-1, and TGF-β1 contribute to fibrosis.

SMAD3 mediates acute and chronic changes in gene expression that lead to inflammation and fibrosis. Chronic exposure to ANG II increases expression of TGF-β1. This cytokine promotes a profibrotic environment by multiple mechanisms, including stimulation of SMAD3-dependent gene expression in smooth muscle cells and monocytes and increased expression of ET-1 by endothelial cells. ET-1 promotes fibroblast activation by stimulating connective tissue growth factor (CTGF) expression and activating an NF-κB–dependent gene program that is profibrotic.