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.
Jiang
Weina
W
Department of Pathology, Ministry of Education of China, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Zhang
Yan
Y
Wu
Huijuan
H
Zhang
Xin
X
Gan
Hualei
H
Sun
Jianyong
J
Chen
Qi
Q
Guo
Muyi
M
Zhang
Zhigang
Z
D000818:Animals; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D050527:Mesangial Cells / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D051899:Smad2 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D024141:Collagen Type IV; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4