Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-beta1 in human renal epithelial cells.
Histone acetylation plays an important role in regulating gene expressions by modulating chromatin structure. Histone deacetylase (HDAC) inhibitors have been reported to have an antifibrogenic effect in some organs, such as the liver, skin, and lung, but the underlying mechanisms remain to be clarified. In the kidney, bone morphologic protein 7 (BMP-7) and hepatocyte growth factor are reported to antagonize TGF-beta1-induced tubular epithelial-to-mesenchymal transition (EMT), but nothing is known concerning the effect of HDAC inhibitors on EMT. It was shown that trichostatin A (TSA), an HDAC inhibitor, prevented TGF-beta1-induced EMT in cultured human renal proximal tubular epithelial cells. Treatment with TGF-beta1 induced morphologic changes such as EMT in human renal proximal tubular epithelial cells. However, co-treatment with TSA completely prevented TGF-beta1-induced morphologic changes and significantly prevented TGF-beta1-induced downregulation of E-cadherin and upregulation of collagen type I. Treatment with TSA did not alter TGF-beta1-induced phosphorylation of Smad2 and Smad3 but induced several inhibitory factors of TGF-beta1 signals, such as inhibitors of DNA binding/differentiation 2 (Id2) and BMP-7. Chromatin immunoprecipitation assay confirmed that histone acetylation was involved in the downregulation of E-cadherin and upregulation of Id2 and BMP-7. These results suggest that TSA and other HDAC inhibitors could be new therapeutic agents for tubular EMT.
Yoshikawa
Masahiro
M
Department of Internal Medicine, Division of Nephrology and Endocrinology, The University Hospital of Tokyo, Tokyo 113-8655, Japan.
Hishikawa
Keiichi
K
Marumo
Takeshi
T
Fujita
Toshiro
T
D001483:Base Sequence; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D015820:Cadherins; D024042:Collagen Type I; D017931:DNA Primers; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C012589:trichostatin A