Abstract
Tubulointerstitial fibrosis (TIF) is the final common pathway in the end-stage renal disease. Epithelial-to-mesenchymal transition (EMT) is considered a major contributor to the TIF by increasing the number of myofibroblasts. Curcumin, a polyphenolic compound derived from rhizomes of Curcuma, has been shown to possess potent anti-fibrotic properties but the mechanism remains elusive. We found that curcumin inhibited the EMT as assessed by reduced expression of α-SMA and PAI-1, and increased E-cadherin in TGF-β1 treated proximal tubular epithelial cell HK-2 cells. Both of the conventional TGF-β1/Smad pathway and non-Smad pathway were investigated. Curcumin reduced TGF-β receptor type I (TβR-I) and TGF-β receptor type II (TβR II), but had no effect on phosphorylation of Smad2 and Smad3. On the other hand, in non-Smad pathway curcumin reduced TGF-β1-induced ERK phosphorylation and PPARγ phosphorylation, and promoted nuclear translocation of PPARγ. Further, the effect of curcumin on α-SMA, PAI-1, E-cadherin, TβR I and TβR II were reversed by ERK inhibitor U0126 or PPARγ inhibitor BADGE, or PPARγ shRNA. Blocking PPARγ signaling pathway by inhibitor BADGE or shRNA had no effect on the phosphorylation of ERK whereas the suppression of ERK signaling pathway inhibited the phosphorylation of PPARγ. We conclude that curcumin counteracted TGF-β1-induced EMT in renal tubular epithelial cells via ERK-dependent and then PPARγ-dependent pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Butadienes / pharmacology
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Cadherins / metabolism
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Curcumin / pharmacology*
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Epithelial Cells / drug effects
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Epithelial Cells / enzymology
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Epithelial Cells / metabolism*
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Epithelial-Mesenchymal Transition / drug effects*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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HEK293 Cells
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Humans
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Kidney Tubules, Proximal / cytology*
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Nitriles / pharmacology
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PPAR gamma / metabolism*
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Phosphorylation / drug effects
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Plasminogen Activator Inhibitor 1 / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / metabolism
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Protein Transport / drug effects
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Rats
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction / drug effects
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Smad Proteins / metabolism*
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Transforming Growth Factor beta1 / pharmacology*
Substances
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Butadienes
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Cadherins
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Nitriles
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PPAR gamma
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Plasminogen Activator Inhibitor 1
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Protein Kinase Inhibitors
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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Transforming Growth Factor beta1
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U 0126
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Protein Serine-Threonine Kinases
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Extracellular Signal-Regulated MAP Kinases
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Tgfbr1 protein, rat
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Curcumin
Grants and funding
This research was supported by Natural Science Foundation of Shanghai (NO.11ZR1433200), Science Foundation of Shanghai Education Commission (NO.2010JW61), Science and Technology of Putuo District, Shanghai (NO.2008PTKW010) and the Innovation Team of the College of the Shanghai Municipal Education Commission, China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.