Downregulation of catalase by reactive oxygen species via PI 3 kinase/Akt signaling in mesangial cells

Reactive oxygen species (ROS) contribute to many glomerular diseases by targeting mesangial cells. ROS have been shown to regulate expression of many antioxidant enzymes including catalase. The mechanism by which the expression of catalase protein is regulated by ROS is not precisely known. Here we report that increased intracellular ROS level by hydrogen peroxide (H2O2) reduced the expression of catalase. H2O2 increased phosphorylation of Akt kinase in a dose-dependent and sustained manner with a concomitant increase in the phosphorylation of FoxOI transcription factor. Further analysis revealed that H2O2 promoted rapid activation of phosphatidylinositol (PI) 3 kinase. The PI 3 kinase inhibitor Ly294002 and expression of tumor suppressor protein PTEN inhibited Akt kinase activity, resulting in the attenuation of FoxOI phosphorylation and preventing the downregulating effect of H2O2 on catalase protein level. Dominant negative Akt attenuated the inhibitory effect of H2O2 on expression of catalase. Constitutively active FoxOI increased the expression of catalase. However, dominant negative FoxOI inhibited catalase protein level. Catalase transcription was reduced by H2O2 treatment. Furthermore, expression of dominant negative Akt and constitutively active FoxOI increased catalase transcription, respectively. These results demonstrate that ROS downregulate the expression of catalase in mesangial cells by PI3 kinase/Akt signaling via FoxOI as a target.