Figure 8.

Proposed model to explain how COX-2 might be essential in the stimulatory pathway for ROS production and increased expression of profibrotic genes mediated by PRR activation. Stimulation of PRR by prorenin or renin activates ERK1/2 phosphorylation leading to COX-2 and NOX-4 upregulation. Our data also suggest that upregulation of NOX-4 depends on both the MAPK pathway and activation of EP4 receptor. ROS formation also depends on NOX-4 activity and EP4 signaling, and ROS is responsible for TGF-β upregulation and activation of Smad pathway through TGF-β receptor. This would then lead to CTGF and PAI-I upregulation. Targeting COX-2-mediated prostaglandin E2 (PGE₂) synthesis may reduce NOX-4 activity and ROS production.