Journal
TRANSLATIONAL RESEARCH
Volume 158, Issue 4, Pages 214-224Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.trsl.2011.06.002
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Funding
- National Science Council of Taiwan [NSC 93-2314-B-037-051, NSC-96-2628-B-037-001-MY3]
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Transforming growth factor-beta (TGF-beta), TGF-beta receptor (TGF-beta R), 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-beta 1-induced mitogenesis and collagen production in normal rat kidney interstitial fibroblast (NRK-49F) cells. We found that TGF-beta 1 increased cell mitogenesis. TGF-beta 1 also time-dependently increased cyclin DI protein expression. TGF-beta 1 rapidly transactivated EGFR. SB431542 (a type I TGF-beta R kinase inhibitor) and SB203580 (a p38 kinase inhibitor) attenuated TGF-beta 1-induced phosphorylation of Smad2/3 protein. SB431542 and gefitinib attenuated TGF-beta 1-induced phosphorylation of ERKI/2 and p38 kinase. SB431542 and gefitinib also attenuated TGF-beta 1-induced cyclin DI protein expression. Moreover, SB431542, gefitinib, PD98059 (an ERK1/2 inhibitor), and SB203580 attenuated TGF-beta 1-induced cell mitogenesis. Finally, SB431542 and gefitinib attenuated TGF-beta 1-induced collagen production. We concluded that gefitinib attenuates TGF-beta 1-induced cell mitogenesis via the EGFR-ERKI/2/p38 kinase pathway in NRK-49F cells. Moreover, gefitinib attenuates TGF-beta 1-induced cyclin DI protein expression and collagen production. Thus, gefitinib attenuates TGF-beta 1-induced mitogenesis and collagen production in vitro. (Translational Research 2011;158:214-224)
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