Identification of histone deacetylase 8 as a novel therapeutic target for renal fibrosis.

Histone deacetylases (HDACs) have been shown to alleviate renal fibrosis, however, the role of individual HDAC isoforms in this process is poorly understood. In this study, we examined the role of HDAC8 in the development of renal fibrosis and partial epithelial-mesenchymal transitions (EMT). In a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), HDAC8 was primarily expressed in renal tubular epithelial cells and time-dependently upregulated. This occurred in parallel with the deacetylation of cortactin, a nonhistone substrate of HDAC8, and increased expression of three fibrotic markers: α-smooth muscle actin, collagen 1, and fibronectin. Administration of PCI34051, a highly selective inhibitor of HDAC8, restored acetylation of contactin and reduced expression of those proteins. PCI34051 treatment also reduced the number of renal tubular epithelial cells arrested at the G2/M phase of the cell cycle and suppressed phosphorylation of Smad3, STAT3, β-catenin, and expression of Snail after ureteral obstruction. In contrast, HDAC8 inhibition reversed UUO-induced downregulation of BMP7 and Klotho, two renoprotective proteins. In cultured murine proximal tubular cells, treatment with PCI34051 or specific HDAC8 siRNA was also effective in inhibiting transforming growth factor β1 (TGFβ1)-induced deacetylation of contactin, EMT, phosphorylation of Smad3, STAT3, and β-catenin, upregulation of Snail, and downregulation of BMP7 and Klotho. Collectively, these results suggest that HDAC8 activation is required for the EMT and renal fibrogenesis by activation of multiple profibrotic signaling and transcription factors, and suppression of antifibrotic proteins. Therefore, targeting HDAC8 may be novel therapeutic approach for treatment of renal fibrosis.

Zhang Y ，Zou J ，Tolbert E ，Zhao TC ，Bayliss G ，Zhuang S ... -  《-》

Blocking the class I histone deacetylase ameliorates renal fibrosis and inhibits renal fibroblast activation via modulating TGF-beta and EGFR signaling.

Liu N ，He S ，Ma L ，Ponnusamy M ，Tang J ，Tolbert E ，Bayliss G ，Zhao TC ，Yan H ，Zhuang S ... -  《PLoS One》

Selective inhibition of class IIa histone deacetylases alleviates renal fibrosis.

Xiong C ，Guan Y ，Zhou X ，Liu L ，Zhuang MA ，Zhang W ，Zhang Y ，Masucci MV ，Bayliss G ，Zhao TC ，Zhuang S ... -  《-》

Class I HDACs specifically regulate E-cadherin expression in human renal epithelial cells.

Epithelial-mesenchymal transition (EMT) and renal fibrosis are closely involved in chronic kidney disease. Inhibition of histone deacetylase (HDAC) has an anti-fibrotic effect in various diseases. However, the pathophysiological role of isoform-specific HDACs or class-selective HDACs in renal fibrosis remains unknown. Here, we investigated EMT markers and extracellular matrix (ECM) proteins in a human proximal tubular cell line (HK-2) by using HDAC inhibitors or by knockdown of class I HDACs (HDAC1, 2, 3 and 8). Trichostatin A (TSA), MS275, PCI34051 and LMK235 inhibited ECM proteins such as collagen type I or fibronectin in transforming growth factor β1 (TGF-β1)-induced HK2 cells. However, restoration of TGF-β1-induced E-cadherin down-regulation was only seen in HK-2 cells treated with TSA or MS275, but not with PCI34051, whereas TGF-β1-induced N-cadherin expression was not affected by the inhibitors. ECM protein and EMT marker levels were prevented or restored by small interfering RNA transfection against HDAC8, but not against other class I HDACs (HDAC1, 2 and 3). E-cadherin regulation is mediated by HDAC8 expression, but not by HDAC8 enzyme activity. Thus, class I HDACs (HDAC1, 2, 3 and 8) play a major role in regulating ECM and EMT, whereas class IIa HDACs (HDAC4 and 5) are less effective.

Choi SY ，Kee HJ ，Kurz T ，Hansen FK ，Ryu Y ，Kim GR ，Lin MQ ，Jin L ，Piao ZH ，Jeong MH ... -  《-》

Piceatannol Attenuates Renal Fibrosis Induced by Unilateral Ureteral Obstruction via Downregulation of Histone Deacetylase 4/5 or p38-MAPK Signaling.

Choi SY ，Piao ZH ，Jin L ，Kim JH ，Kim GR ，Ryu Y ，Lin MQ ，Kim HS ，Kee HJ ，Jeong MH ... -  《PLoS One》