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Role of Reactive Oxygen Species in TGF-1-Induced Mitogen-Activated Protein Kinase Activation and Epithelial-Mesenchymal Transition in Renal Tubular Epithelial Cells

Dong Young Rhyu^*,, Yanqiang Yang^*,, Hunjoo Ha^*,, Geun Taek Lee^*, Jae Sook Song^*, Soo-taek Uh^* and Hi Bahl Lee^*

^* Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea; Department of Medicinal Plant Resources, Mokpo National University, Jeonnam, Korea; National Institute of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; and Ewha Womans University College of Pharmacy, Seoul, Korea

Address correspondence to: Dr. Hunjoo Ha, Ewha Womans University College of Pharmacy, 11-1 Daehyun-dong, Sedaimun-gu, Seoul 120-750, Korea. Phone: +82-2-3277-4075; Fax: +82-2-3277-2851; E-mail: ha{at}hkl.ac.kr or hha{at}ewha.ac.kr

Epithelial-mesenchymal transition (EMT) plays an important role in renal tubulointerstitial fibrosis and TGF-1 is the key inducer of EMT. Phosphorylation of Smad proteins and/or mitogen-activated protein kinases (MAPK) is required for TGF-1–induced EMT. Because reactive oxygen species (ROS) are involved in TGF-1 signaling and are upstream signaling molecules to MAPK, this study examined the role of ROS in TGF-1–induced MAPK activation and EMT in rat proximal tubular epithelial cells. Growth-arrested and synchronized NRK-52E cells were stimulated with TGF-1 (0.2 to 20 ng/ml) or H₂O₂ (1 to 500 µM) in the presence or absence of antioxidants (N-acetylcysteine or catalase), inhibitors of NADPH oxidase (diphenyleneiodonium and apocynin), mitochondrial electron transfer chain subunit I (rotenone), and MAPK (PD 98059, an MEK [MAP kinase/ERK kinase] inhibitor, or p38 MAPK inhibitor) for up to 96 h. TGF-1 increased dichlorofluorescein-sensitive cellular ROS, phosphorylated Smad 2, p38 MAPK, extracellular signal-regulated kinases (ERK)1/2, -smooth muscle actin (-SMA) expression, and fibronectin secretion and decreased E-cadherin expression. Antioxidants effectively inhibited TGF-1–induced cellular ROS, phosphorylation of Smad 2, p38 MAPK, and ERK, and EMT. H₂O₂ reproduced all of the effects of TGF-1 with the exception of Smad 2 phosphorylation. Chemical inhibition of ERK but not p38 MAPK inhibited TGF-1–induced Smad 2 phosphorylation, and both MAPK inhibitors inhibited TGF-1- and H₂O₂-induced EMT. Diphenyleneiodonium, apocynin, and rotenone also significantly inhibited TGF-1–induced ROS. Thus, this data suggest that ROS play an important role in TGF-1–induced EMT primarily through activation of MAPK and subsequently through ERK-directed activation of Smad pathway in proximal tubular epithelial cells.

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