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Inhibition of Histone Deacetylase Activity Suppresses Epithelial-to-Mesenchymal Transition Induced by TGF-1 in Human Renal Epithelial Cells

Department of Internal Medicine, Division of Nephrology and Endocrinology, and Department of Clinical Renal Regeneration, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

Address correspondence to: Dr. Keiichi Hishikawa, Department of Internal Medicine, Division of Nephrology and Endocrinology, The University Hospital of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: +81-3-3815-5411 ext. 35725; Fax: +81-3-5800-9738; E-mail: hishikawa-tky{at}umin.ac.jp

Received for publication November 15, 2005. Accepted for publication October 5, 2006.

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-1–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-1–induced EMT in cultured human renal proximal tubular epithelial cells. Treatment with TGF-1 induced morphologic changes such as EMT in human renal proximal tubular epithelial cells. However, co-treatment with TSA completely prevented TGF-1–induced morphologic changes and significantly prevented TGF-1–induced downregulation of E-cadherin and upregulation of collagen type I. Treatment with TSA did not alter TGF-1–induced phosphorylation of Smad2 and Smad3 but induced several inhibitory factors of TGF-1 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.

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