Role of mitogen-activated protein kinases as downstream effectors of transforming growth factor-beta in mesangial cells.

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates cell proliferation, differentiation, and production of extracellular matrix proteins in various types of cells including mesangial cells. Although TGF-beta has been also known as an important player in the pathogenesis of various fibrotic diseases including glomerulosclerosis, signal-transduction cascades of TGF-beta have remained to be clarified. However, emerging evidence indicates that TGF-beta can activate various signal transduction cascades such as Smad proteins and mitogen-activated protein kinases (MAPKs) in many types of cells. Here, we examine the role of MAPKs in TGF-beta-induced gene expression of extracellular matrix proteins in mesangial cells. TGF-beta increases extracellular signal-regulated kinase (ERK) activity, one of the MAPKs, and the expression of fibronectin mRNA and protein in rat mesangial cells. Furthermore, PD98059, a specific inhibitor of MAPK/ERK kinase (MEK), can inhibit this TGF-beta-induced fibronectin expression. These data suggest that MAPKs play an important role in TGF-beta-mediated extracellular matrix production in mesangial cells.