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Effects of tranilast on the epithelial-to-mesenchymal transition in peritoneal mesothelial cells.

ABSTRACT: Background:We investigated the effects of tranilast on epithelial-to-mesenchymal transition (EMT) in an animal model and on the EMT signaling pathway in human peritoneal mesothelial cells (HPMCs). Methods:We performed in vitro studies (cytotoxicity, cell morphology, and western blot analyses) on HPMCs from human omenta, along with in vivo studies (peritoneal membrane function and morphometric and immunohistochemical analyses) on Sprague Dawley rats. Thirty-two rats were divided into three groups: control (C) group (peritoneal dialysis [PD] catheter but not infused with dialysate), PD group (4.25% glucose-containing dialysate), and PD + tranilast group (4.25% glucose-containing dialysate along with tranilast). Results:In in vitro experiments, transforming growth factor-beta 1 (TGF-?1) increased ?-smooth muscle actin and Snail expression and reduced E-cadherin expression in HPMCs. TGF-?1 also reduced cell contact, induced a fibroblastoid morphology, and increased phosphorylation of Akt, Smad2, and Smad3 in HPMCs. Tranilast significantly inhibited TGF-?1-induced EMT and attenuated these morphological changes in HPMCs. In in vivo studies, after 6 weeks of experimental PD, the peritoneal membrane was significantly thicker in the PD group than in the C group. Tranilast protected against PD-induced glucose mass transfer change and histopathological changes in rats. Conclusion:Tranilast prevented EMT both in HPMCs triggered with TGF-?1 and in rats with PD-induced peritoneal fibrosis. Thus, tranilast may be considered a therapeutic intervention that enables long-term PD by regulating TGF-?1 signaling pathways.

SUBMITTER: Kang SH

PROVIDER: S-EPMC6913598 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Effects of tranilast on the epithelial-to-mesenchymal transition in peritoneal mesothelial cells.

Kang Seok Hui SH Kim Sang Woon SW Kim Keuk Jun KJ Cho Kyu Hyang KH Park Jong Won JW Kim Chan-Duck CD Do Jun Young JY

Kidney research and clinical practice 20191201 4

<h4>Background</h4>We investigated the effects of tranilast on epithelial-to-mesenchymal transition (EMT) in an animal model and on the EMT signaling pathway in human peritoneal mesothelial cells (HPMCs).<h4>Methods</h4>We performed <i>in vitro</i> studies (cytotoxicity, cell morphology, and western blot analyses) on HPMCs from human omenta, along with <i>in vivo</i> studies (peritoneal membrane function and morphometric and immunohistochemical analyses) on Sprague Dawley rats. Thirty-two rats w ...[more]

PMID: 31554027

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Project description:Peritoneal fibrosis (PF), a common complication in patients receiving peritoneal dialysis (PD), is primarily caused by the epithelial-mesenchymal transition (EMT) of human peritoneal mesothelial cells (HPMCs). PF is the main reason for patients on PD to withdraw from PD. Effective treatment is unavailable for this complication at present. Elabela (ELA) is a polypeptide hormone secreted by the vascular endothelium and kidney. Peptide hormones ELA and apelin (APLN) have various protective effects on the cardiovascular and urinary systems and have potential therapeutic effects on organ fibrosis. ELA and APLN are less studied in PD population. Here, we aimed to investigate the clinical significance of ELA in patients on PD and to evaluate the therapeutic effect of ELA on EMT of HPMCs. Compared with those in patients with stage 5 chronic kidney disease who are not on dialysis, serum ELA levels in patients on PD increased with the improvement of residual renal function at PD duration <36 months and decreased to pre-dialysis levels at PD duration ≥36 months, suggesting that dialysis duration is the main risk factor affecting serum ELA levels in patients on PD. In addition, serum APLN levels decreased in the early stage of PD and recovered to the pre-dialysis level with the prolongation of dialysis time. Notably, serum APLN levels were positively correlated with dialysis duration in patients undergoing PD. To establish the EMT model, we stimulated HPMCs using transforming growth factor-beta 1 (TGF-β1) in cell experiments performed in vitro. ELA-32 treatment reversed the TGF-β1-induced reduction in the expression of the epithelial cell marker and suppressed the expression of mesenchymal cell markers by inhibiting the phosphorylation of SMAD2/3, ERK1/2, and AKT. Therefore, our findings imply that ELA-32 can interfere with the EMT of HPMCs by inhibiting the activation of the TGF-β/SMAD2/3, ERK1/2, and AKT pathways, providing novel insights on the potential therapeutic use of ELA for treating PD-related PF.

Dataset Information

Effects of tranilast on the epithelial-to-mesenchymal transition in peritoneal mesothelial cells.

Publications

Effects of tranilast on the epithelial-to-mesenchymal transition in peritoneal mesothelial cells.

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