Dataset Information

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

ABSTRACT: 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 ?1 (TGF-?1)-induced HK2 cells. However, restoration of TGF-?1-induced E-cadherin down-regulation was only seen in HK-2 cells treated with TSA or MS275, but not with PCI34051, whereas TGF-?1-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.

SUBMITTER: Choi SY

PROVIDER: S-EPMC5134402 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Choi Sin Y SY Kee Hae J HJ Kurz Thomas T Hansen Finn K FK Ryu Yuhee Y Kim Gwi R GR Lin Ming Q MQ Jin Li L Piao Zhe H ZH Jeong Myung H MH

Journal of cellular and molecular medicine 20160715 12

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 (HD ...[more]

PMID: 27420561

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Project description:BackgroundRenal tubular epithelial cells of proximal and distal origin differ markedly in their physiological functions. Therefore, we hypothesized that they also differ in their capacity to undergo epithelial to mesenchymal alterations.ResultsWe used cultures of freshly isolated primary human tubular cells. To distinguish cells of different tubular origin we took advantage of the fact that human proximal epithelial cells uniquely express N-cadherin instead of E-cadherin as major cell-cell adhesion molecule. To provoke mesenchymal alteration we treated these cocultures with TGF-? for up to 6 days. Within this time period, the morphology of distal tubular cells was barely altered. In contrast to tubular cell lines, E-cadherin was not down-regulated by TGF-?, even though TGF-? signal transduction was initiated as demonstrated by nuclear localization of Smad2/3. Analysis of transcription factors and miRNAs possibly involved in E-cadherin regulation revealed high levels of miRNAs of the miR200-family, which may contribute to the stability of E-cadherin expression in human distal tubular epithelial cells. By contrast, proximal tubular epithelial cells altered their phenotype when treated with TGF-?. They became elongated and formed three-dimensional structures. Rho-kinases were identified as modulators of TGF-?-induced morphological alterations. Non-specific inhibition of Rho-kinases resulted in stabilization of the epithelial phenotype, while partial effects were observed upon downregulation of Rho-kinase isoforms ROCK1 and ROCK2. The distinct reactivity of proximal and distal cells was retained when the cells were cultured as polarized cells.ConclusionsInterference with Rho-kinase signaling provides a target to counteract TGF-?-mediated mesenchymal alterations of epithelial cells, particularly in proximal tubular epithelial cells. Furthermore, primary distal tubular cells differed from cell lines by their high phenotypic stability which included constant expression of E-cadherin. Our cell culture system of primary epithelial cells is thus suitable to understand and modulate cellular remodeling processes of distinct tubular cells relevant for human renal disease.

Dataset Information

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

Publications

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

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