Class I <scp>HDAC</scp>s specifically regulate E‐cadherin expression in human renal epithelial cells

Choi, Sin Young; Kee, Hae Jin; Kurz, Thomas; Hansen, Finn K.; Ryu, Yuhee; Kim, Gwi R.; Lin, Ming Quan; Jin, Li; Piao, Zhe; Jeong, Myung Ho

doi:10.1111/jcmm.12919

Cited by 32 publications

(21 citation statements)

References 31 publications

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“…However, we did not observe the inhibitory effect of PCI34051 on the downregulation of E‐cadherin, an epithelial marker (data not shown). These results agree with a previous observation that restoration of TGFβ1‐induced E‐cadherin downregulation was not seen in renal epithelial cells treated with PCI34051 25 …”

Section: Resultssupporting

confidence: 93%

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

et al. 2020

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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.

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Section: Resultssupporting

confidence: 93%

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

et al. 2020

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“…Furthermore, HDAC inhibitors suppress fibrosis in organs such as the heart and kidneys [11,12] as shown in vivo as well as in vitro , suggesting that HDACs may be therapeutic targets for treating fibrosis. For example, class I HDACs are activated in transforming growth factor β1- (TGF-β1) treated kidney epithelial cells [13] and are involved in the development of EMT and the ECM in fibrosis with [14] or without [15] diabetes. HDAC6, a class IIb HDAC, may be a target for hypertension-induced kidney fibrosis [16].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Piceatannol, a resveratrol metabolite, is a phenolic compound found in red wine and grapes. We investigated the effect of piceatannol on renal fibrosis and histone deacetylase (HDAC) expression in a mouse model of unilateral ureteral obstruction (UUO). Fibrosis was established by UUO and piceatannol was intraperitoneally injected for 2 weeks. Piceatannol suppressed extracellular matrix (ECM) protein deposition including collagen type I and fibronectin as well as connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA) in UUO kidneys. However, the expressions of epithelial-mesenchymal transition (EMT) marker genes, such as N-cadherin and E-cadherin, were not changed in the kidneys after UUO. Masson’s trichrome staining and fluorescence immunostaining showed that piceatannol administration attenuated collagen deposition in UUO kidneys. HDAC1, HDAC4, HDAC5, HDAC6, and HDAC10 protein expression was upregulated in UUO kidneys, whereas that of HDAC8 was downregulated. Piceatannol treatment significantly reduced HDAC4 and HDAC5 protein expression. Further, piceatannol attenuated phosphorylation of p38 mitogen-activated protein kinase (p38-MAPK) in UUO kidneys, but not that of transforming growth factor beta1-Smad2/3. These results suggest that class I HDACs and class IIa/b HDACs are involved in renal fibrosis development. Piceatannol may be a beneficial therapeutic agent for treating renal fibrosis via reduction of HDAC4 and HDAC5 protein expression or suppression of the p38-MAPK signaling pathway.

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“…However, whether other types of HDACs are involved in ER stress induced EMT needs to be further explored. A very recent study suggested that class I HDACs (HDAC1, 2, 3 and 8) play a major role to regulate EMT of human renal epithelial cells, while class II a HDACs (HDAC4 and 5) are unlikely to be involved [24]. In addition, HDAC inhibitor SB939 inhibited EMT of human renal proximal tubular epithelial cells, and reduced the accumulation of α-SMA and inflammatory and pro-fibrotic cytokines.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylases Promote ER Stress Induced Epithelial Mesenchymal Transition in Human Lung Epithelial Cells

Liu¹,

Zhu²,

Gong³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Epithelial to mesenchymal transition (EMT) is a crucial process involved in pulmonary fibrosis. This study aimed to explore the role of histone deacetylases (HDACs) and endoplasmic reticulum (ER) stress in EMT in human lung epithelial cells. Methods: Human lung adenocarcinoma A549 cells were treated with bleomycin and tunicamycin to induce EMT. The proliferation of A549 cells was detected by MTT assay. The expression of HDACs and EMT markers was detected by PCR and Western blot analysis. The secretion of TGF-β1 and collagen I was examined by ELISA. Results: A549 cells switched from a cobblestone-like appearance to an elongated fibroblast like appearance after exposure to tunicamycin or bleomycin, accompanied by increased expression of N-cadherin, α-SMA and Collagen I. Meanwhile, GRP78 was upregulated in A549 cells exposed to tunicamycin or bleomycin. These changes induced by tunicamycin or bleomycin could be abrogated by 4-PBA. Moreover, tunicamycin and bleomycin promoted the expression of HDAC2 and HDAC6, and HDACs inhibitor SAHA abrogated the morphological and biochemical changes in A549 cells. 4-PBA and SAHA inhibited the upregulation of pulmonary fibrosis factors TGF-β1 and IL-32 and the activation of Smad pathway induced by tunicamycin or bleomycin. Conclusions: We provide the first evidence that tunicamycin and bleomycin induce ER stress and EMT in lung epithelial cells via the upregulation of HDACs. HDACs inhibitor could inhibit ER stress induced upregulation of pulmonary fibrosis factors and the activation of Smad pathway. HDACs inhibitors are promising agents for the therapy of pulmonary fibrosis.

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

Cited by 32 publications

References 31 publications

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

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

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

Histone Deacetylases Promote ER Stress Induced Epithelial Mesenchymal Transition in Human Lung Epithelial Cells

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