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Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-beta1 in human renal epithelial cells.
J Am Soc Nephrol. 2007 Jan; 18(1):58-65.JA

Abstract

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.

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Authors+Show Affiliations

Yoshikawa M
Department of Internal Medicine, Division of Nephrology and Endocrinology, The University Hospital of Tokyo, Tokyo 113-8655, Japan.
Hishikawa K
No affiliation info available
Marumo T
No affiliation info available
Fujita T
No affiliation info available

MeSH

Base SequenceBone Morphogenetic Protein 7Bone Morphogenetic ProteinsCadherinsCells, CulturedCollagen Type IDNA PrimersEnzyme InhibitorsEpithelial CellsHistone Deacetylase InhibitorsHumansHydroxamic AcidsInhibitor of Differentiation Protein 2Kidney Tubules, ProximalMesodermPhosphorylationSmad2 ProteinSmad3 ProteinTransforming Growth Factor beta1Up-Regulation

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17135397

Citation

Yoshikawa, Masahiro, et al. "Inhibition of Histone Deacetylase Activity Suppresses Epithelial-to-mesenchymal Transition Induced By TGF-beta1 in Human Renal Epithelial Cells." Journal of the American Society of Nephrology : JASN, vol. 18, no. 1, 2007, pp. 58-65.
Yoshikawa M, Hishikawa K, Marumo T, et al. Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-beta1 in human renal epithelial cells. J Am Soc Nephrol. 2007;18(1):58-65.
Yoshikawa, M., Hishikawa, K., Marumo, T., & Fujita, T. (2007). Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-beta1 in human renal epithelial cells. Journal of the American Society of Nephrology : JASN, 18(1), 58-65.
Yoshikawa M, et al. Inhibition of Histone Deacetylase Activity Suppresses Epithelial-to-mesenchymal Transition Induced By TGF-beta1 in Human Renal Epithelial Cells. J Am Soc Nephrol. 2007;18(1):58-65. PubMed PMID: 17135397.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-beta1 in human renal epithelial cells. AU - Yoshikawa,Masahiro, AU - Hishikawa,Keiichi, AU - Marumo,Takeshi, AU - Fujita,Toshiro, Y1 - 2006/11/29/ PY - 2006/12/1/pubmed PY - 2007/3/16/medline PY - 2006/12/1/entrez SP - 58 EP - 65 JF - Journal of the American Society of Nephrology : JASN JO - J Am Soc Nephrol VL - 18 IS - 1 N2 - 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. SN - 1046-6673 UR - https://www.unboundmedicine.com/medline/citation/17135397/Inhibition_of_histone_deacetylase_activity_suppresses_epithelial_to_mesenchymal_transition_induced_by_TGF_beta1_in_human_renal_epithelial_cells_ L2 - https://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=17135397 DB - PRIME DP - Unbound Medicine ER -