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Abstract: SA-PO680

Role of Plasminogen Activator Inhibitor-1 (PAI-1) on Phenotype Transition and an Induction of Oxidative Stress in Human Peritoneal Mesothelial Cells (MCs)

Session Information

  • Home Dialysis - II
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Dialysis

  • 802 Dialysis: Home Dialysis and Peritoneal Dialysis

Authors

  • Kang, Duk-Hee, Division of Nephrology, Ewha Womans University College of Medicine, Seoul, Korea (the Republic of)
  • Jo, Chor ho, Hanyang Biomedical Research Institute, Hanyang University College of Medicine, Seoul, Korea (the Republic of)
  • Kim, Dal-Ah, Division of Nephrology, Ewha Womans University College of Medicine, Seoul, Korea (the Republic of)
  • Lee, Minsung, Division of Nephrology, Ewha Womans University College of Medicine, Seoul, Korea (the Republic of)
Background

The epithelial-to-mesenchymal transition (EMT) of MCs is an early mechanism of peritoneal dysfunction in peritoneal dialysis (PD). Plasminogen activator inhibitor-1 (PAI-1) was initially known as an inhibitor of fibrinolysis by hindering the proteolytic activity of tissue type plasminogen activator and urokinase-type plasminogen activator, and recently reported to regulate EMT of cancer cells. However, there are no studies on the role of PAI-1 in peritoneal EMT and fibrosis.

Methods

For in-vitro experiment, EMT was evaluated by morphological changes of MCs and the expression of E-cadherin and α-SMA by real-time PCR, WB and ICC. E-cadherin promoter activity, activation of Smad2/3, Erk1/2, AKT, nuclear translocation of snail and MMP expression were assessed. ROS generation was assessed by DCF-DA, MitoSox staining, and NOX mRNA expression. For in-vivo, PD mouse model (C57BL/6) was established by daily infusion of 4.25% glucose-based dialysate (100mL/kg/day) for 4 weeks via intraperitoneal catheter with or without oral administration of PAI-1 inhibitor (Tiplaxtinin, 5mg/kg/day). In 4 weeks of PD, dialysate/plasma ratio of creatinine (D/PCr) and the 2-hour-dialysate/initial dialysate ratio of glucose (D/D0glu) were measured. Effects of Tiplaxtinin on EMT, peritoneal thickening and an expression of markers of oxidative stress were investigated.

Results

TGFβ (1 ng/ml) stimulation resulted in an increased expression of PAI-1 mRNA and protein in MCs. TGFβ-induced EMT was ameliorated by siPAI-1 or Tiplaxtinin (20 μM). TGFβ-induced nuclear translocation of snail and decrease of E-cadherin promoter activity were also alleviated by siPAI-1. siPAI-1 inhibited TGFβ-induced activation of Smad2/3, Erk1/2, AKT and MMP2 expression. Tiplaxtinin alleviated NOX- and mitochondria-mediated ROS production. In mouse PD model, Tiplaxtinin ameliorated the changes in D/D0glu and D/PCr. Also, Tiplaxtinin administration also resulted in a decrease in peritoneal thickness and fibrosis and an increase in ratio of reduced to oxidized glutathione and SOD2.

Conclusion

PAI-1 plays a role in peritoneal EMT and fibrosis, and modulation of PAI-1 expression/activity in MCs could be a novel strategy to prevent peritoneal fibrosis in PD patients.

Funding

  • Government Support – Non-U.S.