Reactive oxygen species mediate TGF-<f>β1</f>-induced plasminogen activator inhibitor-1 upregulation in mesangial cells

Transforming growth factor-<f>β1</f> (TGF-<f>β1</f>) promotes tissue fibrosis by upregulating genes encoding extracellular matrix proteins and by increasing the synthesis of plasminogen activator inhibitor-1 (PAI-1). TGF-<f>β1</f> induces cellular reactive oxygen species (ROS) and PAI-1 promoter region has binding sites for redox sensitive transcription factors. We, therefore, hypothesized that TGF-<f>β1</f>-induced upregulation of PAI-1 is ROS-dependent. Using cultured glomerular mesangial cells, we confirmed that TGF-<f>β1</f> induces cellular ROS, upregulates PAI-1 mRNA and protein expression, and suppresses plasmin activity. We further demonstrated that H2O2 stimulates PAI-1 expression and suppresses plasmin activity and that N-acetylcysteine effectively reverses TGF-<f>β1</f>- and H2O2-induced changes in PAI-1 expression and plasmin activity. Basal as well as TGF-<f>β1</f>- and H2O2-induced PAI-1 expression was upregulated by depletion of intracellular GSH. The present data demonstrate that TGF-<f>β1</f>-induced PAI-1 in mesangial cells is ROS-dependent and imply that cellular ROS may be potential therapeutic targets in glomerular fibrosis. [Copyright &y& Elsevier]