Role of cross-talk between the Smad2 and MAPK pathways in TGF-beta1-induced collagen IV expression in mesangial cells.

Transforming growth factor beta1 (TGF-beta1) can promote sclerosis in many kidney diseases by enhancing the synthesis of collagens. However, the mechanisms of down-stream intracellular signal transduction in TGF-beta1-induced collagen synthesis is not fully understood. The purpose of this study was to further investigate the mechanisms and the cross-talk between the MAPK and Smad2 pathways. We found that U0126, a specific inhibitor of ERK1/2, and SB203580, a specific inhibitor of p38, down-regulated the TGF-beta1-induced phosphorylation of Smad2 at both linker and C-terminal sites in rat mesangial cells. Whereas, SP600125, a specific inhibitor of JNK, only down-regulated the phosphorylation of Smad2 at the C-terminal sites, but had little effect on the phosphorylation of Smad2 at linker sites. However, all three MAPK inhibitors reduced collagen IV synthesis induced by TGF-beta1. Furthermore, TGF-beta1 induced the phosphorylation of Smad2 at both the linker and C-terminal sites. Transient transfection of a dominant negative Smad2 construct significantly decreased TGF-beta1-induced phosphorylation of ERK1/2, JNK and expression of collagen IV, but did not decrease the phosphorylation of p38. These findings demonstrate that there is cross-talk between the MAPK (ERK1/2, JNK, p38) and Smad2 pathways, and that the cross-talk interacts mutually to enhance the synthesis of collagen IV in rat mesangial cells.