Maladaptive activation of the renin angiotensin system (RAS) has been shown to play a critical role in the pathogenesis of chronic kidney disease. Reactive oxygen species (ROS) are critical signals for many of the non-hemodynamic effects of Angiotensin II (Ang II). We have demonstrated that Ang II increases mesangial and cortical COX-2 expression and activity via NADPH oxidase derived ROS. The transcription factor ETS-1 has been identified as a critical regulator of growth related responses and inflammation. The current studies were designed to determine: 1) whether Ang II induces ETS-1 expression in vitro in cultured rat mesangial cells (MC) and in vivo in rats infused with Ang II and 2) To determine if ROS and COX-2 are mediators of ETS-1 induction in response to Ang II. MC stimulated with Ang II (10^-7 M) exhibited a significant increase in ETS-1 expression that was prevented by the AT1 receptor blocker candesartan. NADPH oxidase inhibition with DPI or apocynin also prevented ETS-1 induction, establishing the role of ROS as mediators of ETS-1 expression in response to Ang II. COX-2 inhibition prevented ETS-1 expression in response to Ang II suggesting that COX-2 is required for ETS-1 induction. By utilizing siRNAs against ETS-1 we have also determined that ETS-1 is required to induce the production of fibronectin in response to Ang II. Furthermore, rats infused with Ang II manifested increased glomerular expression of ETS-1. These studies unveil novel pathways that may play an important role in the pathogenesis of renal injury when RAS is activated.