Gefitinib attenuates transforming growth factor-β1-activated mitogen-activated protein kinases and mitogenesis in NRK-49F cells

San-Cher Chen, Jinn-Yuh Guh, Tai-Du Lin, Shean-Jaw Chiou, Chi-Ching Hwang, Yu-Min Ko, Lea-Yea Chuang
Translational Research: the Journal of Laboratory and Clinical Medicine 2011, 158 (4): 214-24
Transforming growth factor-β (TGF-β), TGF-β receptor (TGF-βR), and epidermal growth factor receptor (EGFR) are important in the pathogenesis of kidney fibrosis, a result of renal fibroblast activation. The EGFR kinase inhibitor gefitinib attenuates glomerular fibrosis in hypertensive rats whereas dominant-negative EGFR attenuates interstitial fibrosis in mouse with acute renal ischemia. Thus, we studied the effects and molecular mechanisms of gefitinib in TGF-β1-induced mitogenesis and collagen production in normal rat kidney interstitial fibroblast (NRK-49F) cells. We found that TGF-β1 increased cell mitogenesis. TGF-β1 also time-dependently increased cyclin D1 protein expression. TGF-β1 rapidly transactivated EGFR. SB431542 (a type I TGF-βR kinase inhibitor) and SB203580 (a p38 kinase inhibitor) attenuated TGF-β1-induced phosphorylation of Smad2/3 protein. SB431542 and gefitinib attenuated TGF-β1-induced phosphorylation of ERK1/2 and p38 kinase. SB431542 and gefitinib also attenuated TGF-β1-induced cyclin D1 protein expression. Moreover, SB431542, gefitinib, PD98059 (an ERK1/2 inhibitor), and SB203580 attenuated TGF-β1-induced cell mitogenesis. Finally, SB431542 and gefitinib attenuated TGF-β1-induced collagen production. We concluded that gefitinib attenuates TGF-β1-induced cell mitogenesis via the EGFR-ERK1/2/p38 kinase pathway in NRK-49F cells. Moreover, gefitinib attenuates TGF-β1-induced cyclin D1 protein expression and collagen production. Thus, gefitinib attenuates TGF-β1-induced mitogenesis and collagen production in vitro.

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