title: Arctigenin suppresses transforming growth factor-β1-induced expression of monocyte chemoattractant protein-1 and the subsequent epithelial-mesenchymal transition through reactive oxygen species-dependent ERK/NF-κB signaling pathway in renal tubular epithelial cells.
abstract: Transforming growth factor-β1 (TGF-β1) induces expression of the proinflammatory and profibrotic cytokine monocyte chemoattractant protein-1 (MCP-1) in tubular epithelial cells (TECs) and thereby contributes to the tubular epithelial-mesenchymal transition (EMT), which in turn leads to the progression of tubulointerstitial inflammation into tubulointerstitial fibrosis. Exactly how TGF-β1 causes MCP-1 overexpression and subsequent EMT is not well understood. Using human tubular epithelial cultures, we found that TGF-β1 upregulated the expression of reduced nicotinamide adenine dinucleotide phosphate oxidases 2 and 4 and their regulatory subunits, inducing the production of reactive oxygen species. These reactive species activated a signaling pathway mediated by extracellular signal-regulated kinase (ERK1/2) and nuclear factor-κB (NF-κB), which upregulated expression of MCP-1. Incubating cultures with TGF-β1 was sufficient to induce hallmarks of EMT, such as downregulation of epithelial marker proteins (E-cadherin and zonula occludens-1), induction of mesenchymal marker proteins (α-smooth muscle actin, fibronectin, and vimentin), and elevated cell migration and invasion in an EMT-like manner. Overexpressing MCP-1 in cells exposed to TGF-β1 exacerbated these EMT-like changes. Pretreating cells with the antioxidant and anti-inflammatory compound arctigenin (ATG) protected them against these TGF-β1-induced EMT-like changes; the compound worked by inhibiting the ROS/ERK1/2/NF-κB pathway to decrease MCP-1 upregulation. These findings suggest ATG as a new therapeutic candidate to inhibit or even reverse tubular EMT-like changes during progression to tubulointerstitial fibrosis, and they provide the first clues to how ATG may work.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, College of Pharmacy and Bioengineering, Chongqing University of Technology , Chongqing , P. R. China.
authors.forename: A
authors.initials: A
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Zhu
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Pan
authors.forename: R
authors.initials: R
authors.lastname: Wang
mesh_terms: D015703:Antigens, CD; D000975:Antioxidants / Q000737:chemistry; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D005663:Furans / Q000737:chemistry*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology; D017705:Lignans / Q000737:chemistry*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000975:Antioxidants; C111835:CCL2 protein, human; C513384:CDH1 protein, human; D015820:Cadherins; D018932:Chemokine CCL2; D005663:Furans; D017705:Lignans; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C569042:TJP1 protein, human; D053773:Transforming Growth Factor beta1; D062826:Zonula Occludens-1 Protein; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; C071942:arctigenin
keywords: NADPH oxidase; antioxidant capacity; hydrogen peroxide; redox signaling; redox-sensitive transcription factors