Abstract
Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in a variety of conditions including peritoneal dialysis (PD), post-surgery adhesions and peritoneal metastases. The acquisition of invasive and pro-fibrotic abilities by mesothelial cells (MCs) through induction of MMT, a cell-specific form of EMT, plays a main role in this process. Aim of this study was to evaluate possible effects of histone deacetylase (HDAC) inhibitors, key components of the epigenetic machinery, in counteracting MMT observed in MCs isolated from effluent of PD patients. HDAC inhibitors with different class/isoform selectivity have been used for pharmacological inhibition. While the effect of other inhibitors was limited to a partial E-cadherin re-expression, MS-275, a HDAC1-3 inhibitor, promoted: (i) downregulation of mesenchymal markers (MMP2, Col1A1, PAI-1, TGFβ1, TGFβRI) (ii) upregulation of epithelial markers (E-cadherin, Occludin), (iii) reacquisition of an epithelial-like morphology and (iv) marked reduction of cellular invasiveness. Results were confirmed by HDAC1 genetic silencing. Mechanistically, MS-275 causes: (i) increase of nuclear histone H3 acetylation (ii) rescue of the acetylation profile on E-cadherin promoter, (iii) Snail functional impairment. Overall, our study, pinpointing a role for HDAC1, revealed a new player in the regulation of peritoneal fibrosis, providing the rationale for future therapeutic opportunities.
Highlights
Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in a variety of conditions including peritoneal dialysis (PD), post-surgery adhesions and peritoneal metastases
We revealed a specific role for class I HDAC1-3, and in particular for HDAC1: its inhibition by treatment with MS-275 compound causes the reversal of mesenchymal transition (MMT)-related marker gene expression and the reacquisition of epithelial-like morphology; treated cells showed a marked reduction in motility
mesothelial cells (MCs) derived from peritoneal effluent of PD patients undergo reversal of MMT-related marker gene expression when treated with MS-275, a selective HDAC1-3 inhibitor
Summary
Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in a variety of conditions including peritoneal dialysis (PD), post-surgery adhesions and peritoneal metastases. The acquisition of invasive and pro-fibrotic abilities by mesothelial cells (MCs) through induction of MMT, a cell-specific form of EMT, plays a main role in this process. Peritoneal fibrosis is a pathological process leading to progressive alteration of peritoneum morphology and functions. MCs have an important role in peritoneal fibrosis due to induction of epithelial to mesenchymal transition (EMT), characterized by acquisition of invasive features and secretion of profibrotic/proangiogenic mediators[5,6,7]. Due to their peculiar features, the transition of MCs has been recently characterized as a mesothelial to mesenchymal transition (MMT)[3]
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