title: A crosstalk between the Smad and JNK signaling in the TGF-β-induced epithelial-mesenchymal transition in rat peritoneal mesothelial cells.
abstract: Transforming growth factor β (TGF-β) induces the process of epithelial-mesenchymal transition (EMT) through the Smad and JNK signaling. However, it is unclear how these pathways interact in the TGF-β1-induced EMT in rat peritoneal mesothelial cells (RPMCs). Here, we show that inhibition of JNK activation by introducing the dominant-negative JNK1 gene attenuates the TGF-β1-down-regulated E-cadherin expression, and TGF-β1-up-regulated α-SMA, Collagen I, and PAI-1 expression, leading to the inhibition of EMT in primarily cultured RPMCs. Furthermore, TGF-β1 induces a bimodal JNK activation with peaks at 10 minutes and 12 hours post treatment in RPMCs. In addition, the inhibition of Smad3 activation by introducing a Smad3 mutant mitigates the TGF-β1-induced second wave, but not the first wave, of JNK1 activation in RPMCs. Moreover, the inhibition of JNK1 activation prevents the TGF-β1-induced Smad3 activation and nuclear translocation, and inhibition of the TGF-β1-induced second wave of JNK activation greatly reduced TGF-β1-induced EMT in RPMCs. These data indicate a crosstalk between the JNK1 and Samd3 pathways during the TGF-β1-induced EMT and fibrotic process in RPMCs. Therefore, our findings may provide new insights into understanding the regulation of the TGF-β1-related JNK and Smad signaling in the development of fibrosis.
authors.affiliation: Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Key Laboratory of Nephrology, Ministry of Health, Guangzhou, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Haiping
authors.initials: H
authors.lastname: Mao
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Ning
authors.initials: N
authors.lastname: Luo
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhou
authors.forename: Wenfang
authors.initials: W
authors.lastname: Chen
authors.forename: Xueqing
authors.initials: X
authors.lastname: Yu
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D058750:Epithelial-Mesenchymal Transition; D004848:Epithelium / Q000378:metabolism*; D005355:Fibrosis; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D009154:Mutation; D056627:Peritoneal Fibrosis / Q000473:pathology; D010537:Peritoneum / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C497790:SMAD3 protein, human; D051785:Smad Proteins; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D048670:MAP Kinase Kinase 4