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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/F729    most recent 00086.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Noh, H. Articles by Lee, H. B. PubMed PubMed Citation Articles by Noh, H. Articles by Lee, H. B.

Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-β1-induced renal injury

¹Hyonam Kidney Laboratory, Soon Chun Hyang University, ²Ewha Womans University College of Pharmacy, and ³Center for Cell Signaling and Drug Discovery Research, Seoul, Korea

Submitted 13 February 2009 ; accepted in final form 21 June 2009

Excessive accumulation of extracellular matrix (ECM) in the kidneys and epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells contributes to the renal fibrosis that is associated with diabetic nephropathy. Histone deacetylase (HDAC) determines the acetylation status of histones and thereby controls the regulation of gene expression. This study examined the effect of HDAC inhibition on renal fibrosis induced by diabetes or transforming growth factor (TGF)-β1 and determined the role of reactive oxygen species (ROS) as mediators of HDAC activation. In streptozotocin (STZ)-induced diabetic kidneys and TGF-β1-treated normal rat kidney tubular epithelial cells (NRK52-E), we found that trichostatin A, a nonselective HDAC inhibitor, decreased mRNA and protein expressions of ECM components and prevented EMT. Valproic acid and class I-selective HDAC inhibitor SK-7041 also showed similar effects in NRK52-E cells. Among the six HDACs tested (HDAC-1 through -5 and HDAC-8), HDAC-2 activity significantly increased in the kidneys of STZ-induced diabetic rats and db/db mice and TGF-β1-treated NRK52-E cells. Levels of mRNA expression of fibronectin and -smooth muscle actin were decreased, whereas E-cadherin mRNA was increased when HDAC-2 was knocked down using RNA interference in NRK52-E cells. Interestingly, hydrogen peroxide increased HDAC-2 activity, and the treatment with an antioxidant, N-acetylcystein, almost completely reduced TGF-β1-induced activation of HDAC-2. These findings suggest that HDAC-2 plays an important role in the development of ECM accumulation and EMT in diabetic kidney and that ROS mediate TGF-β1-induced activation of HDAC-2.

reactive oxygen species; extracellular matrix; epithelial-to-mesenchymal transition