title: Role of reactive oxygen species in transforming growth factor-beta1-induced extracellular matrix accumulation in renal tubular epithelial cells.
abstract: Tubulointerstitial fibrosis, which is characterized by the progressive accumulation of extracellular matrix (ECM), is the main feature of chronic renal allograft dysfunction. Transforming growth factor-β1 (TGF-β1) is the key inducer of tubulointerstitial fibrosis. Plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of ECM degradation, is increasingly recognized to play an important role in renal fibrosis. ECM accumulation is the net result of ECM synthesis and degradation. We previously reported that reactive oxygen species (ROS) and subsequent activation of mitogen-activated protein kinase (MAPK) are required for the TGF-β1-induced epithelial-to-mesenchymal transition in renal proximal tubular epithelial cells. In the present study, we examined the role of the ROS-MAPK pathways in TGF-β1-induced fibronectin and PAI-1 up-regulation in renal tubular epithelial cells. Growth arrested, synchronized normal rat kidney epithelial (NRK-52E) cells were stimulated with TGF-β1 (0.2-20 ng/mL) or H(2)O(2) (1-500 μmol/L) in the presence or absence of inhibitors of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (diphenyleneiodonium [DPI] and apocynin [Apo]) and MAPK (PD98059, an MEK inhibitor, or a p38 MAPK inhibitor) for up to 48 hours. Both TGF-β1 and H(2)O(2) increased fibronectin and PAI-1 secretion in dose-dependent manners. Chemical inhibition of NADPH oxidase, extracellular signal-regulated kinase (ERK), or p38 MAPK all inhibited TGF-β1-induced and H(2)O(2)-induced fibronectin and PAI-1 up-regulation. These results suggested that NADPH oxidase-mediated ROS and subsequent ERK and p38 MAPK activation play important roles in ECM accumulation in the renal tubulointerstitium.
authors.affiliation: Department of Oriental Medicine Resources, Mokpo National University, Jeonnam, Korea.
authors.forename: D Y
authors.initials: DY
authors.lastname: Rhyu
authors.forename: J
authors.initials: J
authors.lastname: Park
authors.forename: B R
authors.initials: BR
authors.lastname: Sharma
authors.forename: H
authors.initials: H
authors.lastname: Ha
mesh_terms: D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007684:Kidney Tubules / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases