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Fibrin-Induced epithelial-to-mesenchymal transition of peritoneal mesothelial cells as a mechanism of peritoneal fibrosis: effects of pentoxifylline.

ABSTRACT: Excessive fibrin deposition in the peritoneum is thought to be involved in the development of encapsulating peritoneal sclerosis (EPS), an important cause of morbidity and mortality in peritoneal dialysis patients. We investigated fibrin-induced epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) as a possible mechanism of fibrin involvement in EPS. In vitro, fibrin overlay of PMCs altered their morphology; increased ?-smooth muscle actin, fibronectin, fibroblast specific protein-1, and ?(v)?(3) integrin expression; and decreased cytokeratin 18 and E-cadherin expression. Fibrin overlay also increased focal adhesion kinase and Src kinase phosphorylation. Fibrin-induced changes were inhibited by treating the cells with ?(v)?(3) integrin antibody or pentoxifylline (PTX). In a rat model, intraperitoneal injection of Staphylococcus aureus and fibrinogen induced severe EPS features, which were attenuated by PTX treatment. PTX-treated rats also showed preserved peritoneal ultrafiltration function and lower concentrations of cytokines than the untreated rats. S. aureus- and fibrinogen-injected rats had higher percentage of cytokeratin-positive cells in the omentum fibrotic tissue than controls; this was also reduced by PTX treatment. Our results suggest that fibrin induces EMT of PMCs by engaging ?(v)?(3) integrin and activating associated kinases. Our EPS animal model showed that fibrin-induced EMT was involved in the pathogenesis of peritoneal fibrosis and was inhibited by PTX.

SUBMITTER: Fang CC

PROVIDER: S-EPMC3441450 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Fibrin-Induced epithelial-to-mesenchymal transition of peritoneal mesothelial cells as a mechanism of peritoneal fibrosis: effects of pentoxifylline.

Fang Cheng-Chung CC Huang Jenq-Wen JW Shyu Ren-Shi RS Yen Chung-Jen CJ Shiao Cheng-Hsiang CH Chiang Chih-Kang CK Hu Rey-Heng RH Tsai Tun-Jun TJ

PloS one 20120913 9

Excessive fibrin deposition in the peritoneum is thought to be involved in the development of encapsulating peritoneal sclerosis (EPS), an important cause of morbidity and mortality in peritoneal dialysis patients. We investigated fibrin-induced epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) as a possible mechanism of fibrin involvement in EPS. In vitro, fibrin overlay of PMCs altered their morphology; increased α-smooth muscle actin, fibronectin, fibroblast sp ...[more]

PMID: 23028611

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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

Fibrin-Induced epithelial-to-mesenchymal transition of peritoneal mesothelial cells as a mechanism of peritoneal fibrosis: effects of pentoxifylline.

Publications

Fibrin-Induced epithelial-to-mesenchymal transition of peritoneal mesothelial cells as a mechanism of peritoneal fibrosis: effects of pentoxifylline.

Similar Datasets

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