Abstract
Epithelial-mesenchymal transition (EMT) is thought to contribute to the progression of renal tubulointerstitial fibrosis. Norcantharidin (NCTD) is a promising agent for inhibiting renal interstitial fibrosis. However, the molecular mechanisms of NCTD are unclear. In this study, a unilateral ureteral obstruction (UUO) rat model was established and treated with intraperitoneal NCTD (0.1 mg/kg/day). The UUO rats treated with NCTD showed a reduction in obstruction-induced upregulation of α-SMA and downregulation of E-cadherin in the rat kidney (P<0.05). Human renal proximal tubule cell lines (HK-2) stimulated with TGF-β1 were treated with different concentrations of NCTD. HK-2 cells stimulated by TGF-β1 in vitro led to downregulation of E-cadherin and increased de novo expression of α-SMA; co-treatment with NCTD attenuated all of these changes (P<0.05). NCTD reduced TGF-β1-induced expression and phosphorylation of Smad2/3 and downregulated the expression of Snail1 (P<0.05). These results suggest that NCTD antagonizes tubular EMT by inhibiting the Smad pathway. NCTD may play a critical role in preserving the normal epithelial phenotype and modulating tubular EMT.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / genetics
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Animals
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Cadherins / genetics
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Cell Line
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Epithelial-Mesenchymal Transition / drug effects*
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Fibrosis
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Gene Expression Regulation / drug effects
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Humans
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Kidney Tubules / drug effects*
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Kidney Tubules / metabolism
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Kidney Tubules / pathology*
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Male
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Phenotype
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Phosphorylation / drug effects
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Smad2 Protein / genetics
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Smad2 Protein / metabolism
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Smad3 Protein / genetics
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Smad3 Protein / metabolism
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Snail Family Transcription Factors
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Transcription Factors / genetics
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Transforming Growth Factor beta1 / metabolism
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Transforming Growth Factor beta1 / pharmacology
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Ureteral Obstruction / genetics
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Ureteral Obstruction / metabolism
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Ureteral Obstruction / pathology
Substances
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Actins
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Bridged Bicyclo Compounds, Heterocyclic
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Cadherins
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SNAI1 protein, human
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Smad2 Protein
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Smad3 Protein
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Snai2 protein, rat
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Snail Family Transcription Factors
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Transcription Factors
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Transforming Growth Factor beta1
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smooth muscle actin, rat
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norcantharidin
Grants and funding
This study was supported by the National Natural Science Foundation of China (Grant No.81100486), the Natural Science Foundation of Hunan Province of China (Grant No.10JJ2011), and the scientific project of the Research Center of Metabolic Syndrome in Central South University of China (Grant No.DY-2008-02-03). The corresponding author and all the above grand funders played a role in designing and doing the experiment and writing the manuscript.