Inhibition of platelet-derived growth factor-induced mesangial cell proliferation by cyclooxygenase-2 overexpression is abolished through reactive oxygen species.

Proliferation of mesangial cells (MC) is an early event in many forms of glomerulonephritis. We have previously shown that platelet-derived growth factor (PDGF)-induced proliferation of MC was inhibited by the overexpression of cyclooxygenase-2 (COX-2). Since reactive oxygen species (ROS) are important mediators of mitogenic signaling, we evaluated the role of ROS in the COX-2 induced growth arrest in MC. We demonstrate that ROS are reduced in COX-2 overexpressing MC. Intracellular elevation of ROS restored PDGF-induced proliferation, while the expression of the cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1) were decreased in these cells. The data suggest that COX-2 decreases ROS formation which consequently leads to the PDGF-induced inhibition of MC proliferation.