Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor- 1-induced renal injury

Noh H, Oh EY, Seo JY, Yu MR, Kim YO, Ha H, Lee HB. Histone deacetylase-2 is a key regulator of diabetesand transforming growth factor1-induced renal injury. Am J Physiol Renal Physiol 297: F729 –F739, 2009. First published June 24, 2009; doi:10.1152/ajprenal.00086.2009.—Excessive accumulation of extracellular matrix (ECM) in the kidneys and epithelial-tomesenchymal 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)1 and determined the role of reactive oxygen species (ROS) as mediators of HDAC activation. In streptozotocin (STZ)-induced diabetic kidneys and TGF1-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 STZinduced diabetic rats and db/db mice and TGF1-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 TGF1-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 TGF1-induced activation of HDAC-2.