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Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells.
J Am Soc Nephrol. 2005 Mar; 16(3):667-75.JA

Abstract

Epithelial-mesenchymal transition (EMT) plays an important role in renal tubulointerstitial fibrosis and TGF-beta1 is the key inducer of EMT. Phosphorylation of Smad proteins and/or mitogen-activated protein kinases (MAPK) is required for TGF-beta1-induced EMT. Because reactive oxygen species (ROS) are involved in TGF-beta1 signaling and are upstream signaling molecules to MAPK, this study examined the role of ROS in TGF-beta1-induced MAPK activation and EMT in rat proximal tubular epithelial cells. Growth-arrested and synchronized NRK-52E cells were stimulated with TGF-beta1 (0.2 to 20 ng/ml) or H(2)O(2) (1 to 500 microM) 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-beta1 increased dichlorofluorescein-sensitive cellular ROS, phosphorylated Smad 2, p38 MAPK, extracellular signal-regulated kinases (ERK)1/2, alpha-smooth muscle actin (alpha-SMA) expression, and fibronectin secretion and decreased E-cadherin expression. Antioxidants effectively inhibited TGF-beta1-induced cellular ROS, phosphorylation of Smad 2, p38 MAPK, and ERK, and EMT. H(2)O(2) reproduced all of the effects of TGF-beta1 with the exception of Smad 2 phosphorylation. Chemical inhibition of ERK but not p38 MAPK inhibited TGF-beta1-induced Smad 2 phosphorylation, and both MAPK inhibitors inhibited TGF-beta1- and H(2)O(2)-induced EMT. Diphenyleneiodonium, apocynin, and rotenone also significantly inhibited TGF-beta1-induced ROS. Thus, this data suggest that ROS play an important role in TGF-beta1-induced EMT primarily through activation of MAPK and subsequently through ERK-directed activation of Smad pathway in proximal tubular epithelial cells.

Authors+Show Affiliations

Ewha Womans University College of Pharmacy, 11-1 Daehyun-dong, Sedaimun-gu, Seoul 120-750, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15677311

Citation

Rhyu, Dong Young, et al. "Role of Reactive Oxygen Species in TGF-beta1-induced Mitogen-activated Protein Kinase Activation and Epithelial-mesenchymal Transition in Renal Tubular Epithelial Cells." Journal of the American Society of Nephrology : JASN, vol. 16, no. 3, 2005, pp. 667-75.
Rhyu DY, Yang Y, Ha H, et al. Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. J Am Soc Nephrol. 2005;16(3):667-75.
Rhyu, D. Y., Yang, Y., Ha, H., Lee, G. T., Song, J. S., Uh, S. T., & Lee, H. B. (2005). Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. Journal of the American Society of Nephrology : JASN, 16(3), 667-75.
Rhyu DY, et al. Role of Reactive Oxygen Species in TGF-beta1-induced Mitogen-activated Protein Kinase Activation and Epithelial-mesenchymal Transition in Renal Tubular Epithelial Cells. J Am Soc Nephrol. 2005;16(3):667-75. PubMed PMID: 15677311.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. AU - Rhyu,Dong Young, AU - Yang,Yanqiang, AU - Ha,Hunjoo, AU - Lee,Geun Taek, AU - Song,Jae Sook, AU - Uh,Soo-taek, AU - Lee,Hi Bahl, Y1 - 2005/01/26/ PY - 2005/1/29/pubmed PY - 2005/6/29/medline PY - 2005/1/29/entrez SP - 667 EP - 75 JF - Journal of the American Society of Nephrology : JASN JO - J Am Soc Nephrol VL - 16 IS - 3 N2 - Epithelial-mesenchymal transition (EMT) plays an important role in renal tubulointerstitial fibrosis and TGF-beta1 is the key inducer of EMT. Phosphorylation of Smad proteins and/or mitogen-activated protein kinases (MAPK) is required for TGF-beta1-induced EMT. Because reactive oxygen species (ROS) are involved in TGF-beta1 signaling and are upstream signaling molecules to MAPK, this study examined the role of ROS in TGF-beta1-induced MAPK activation and EMT in rat proximal tubular epithelial cells. Growth-arrested and synchronized NRK-52E cells were stimulated with TGF-beta1 (0.2 to 20 ng/ml) or H(2)O(2) (1 to 500 microM) 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-beta1 increased dichlorofluorescein-sensitive cellular ROS, phosphorylated Smad 2, p38 MAPK, extracellular signal-regulated kinases (ERK)1/2, alpha-smooth muscle actin (alpha-SMA) expression, and fibronectin secretion and decreased E-cadherin expression. Antioxidants effectively inhibited TGF-beta1-induced cellular ROS, phosphorylation of Smad 2, p38 MAPK, and ERK, and EMT. H(2)O(2) reproduced all of the effects of TGF-beta1 with the exception of Smad 2 phosphorylation. Chemical inhibition of ERK but not p38 MAPK inhibited TGF-beta1-induced Smad 2 phosphorylation, and both MAPK inhibitors inhibited TGF-beta1- and H(2)O(2)-induced EMT. Diphenyleneiodonium, apocynin, and rotenone also significantly inhibited TGF-beta1-induced ROS. Thus, this data suggest that ROS play an important role in TGF-beta1-induced EMT primarily through activation of MAPK and subsequently through ERK-directed activation of Smad pathway in proximal tubular epithelial cells. SN - 1046-6673 UR - https://www.unboundmedicine.com/medline/citation/15677311/Role_of_reactive_oxygen_species_in_TGF_beta1_induced_mitogen_activated_protein_kinase_activation_and_epithelial_mesenchymal_transition_in_renal_tubular_epithelial_cells_ L2 - https://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=15677311 DB - PRIME DP - Unbound Medicine ER -