title: Gefitinib attenuates transforming growth factor-β1-activated mitogen-activated protein kinases and mitogenesis in NRK-49F cells.
abstract: 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.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Taiwan, Republic of China.
authors.forename: San-Cher
authors.initials: SC
authors.lastname: Chen
authors.forename: Jinn-Yuh
authors.initials: JY
authors.lastname: Guh
authors.forename: Tai-Du
authors.initials: TD
authors.lastname: Lin
authors.forename: Shean-Jaw
authors.initials: SJ
authors.lastname: Chiou
authors.forename: Chi-Ching
authors.initials: CC
authors.lastname: Hwang
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Ko
authors.forename: Lea-Yea
authors.initials: LY
authors.lastname: Chuang
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D003094:Collagen / Q000096:biosynthesis; D019938:Cyclin D1 / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D000077156:Gefitinib; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D008954:Models, Biological; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D057170:Translational Research, Biomedical; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; C530106:Ccnd1 protein, rat; D004149:Dioxoles; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D011799:Quinazolines; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D019938:Cyclin D1; D003094:Collagen; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D000077156:Gefitinib; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one