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Abstract: SA-PO942

Nuclear Factor of Activated T Cells 5 (NFAT5) Mediates Peritoneal Fibrosis via Modulation of Nod-Like Receptor-3 (NLRP3) Inflammasome

Session Information

Category: Dialysis

  • 703 Dialysis: Peritoneal Dialysis

Authors

  • Kang, Duk-Hee, Ewha University College of Medicine, Seoul, Korea (the Republic of)
  • Ryu, Eun sun, Ewha University College of Medicine, Seoul, Korea (the Republic of)
  • Kim, Dal-ah, Ewha University College of Medicine, Seoul, Korea (the Republic of)
  • Kang, Hyun-Jung, Ewha University College of Medicine, Seoul, Korea (the Republic of)
  • Kim, You Jin, Kyungpook National University, Daegu, Korea (the Republic of)
  • Park, Sun-Hee, Kyungpook National University Hospital, Daegu, Korea (the Republic of)
  • Kim, Yong-Lim, Kyungpook National University Hospital, Daegu, Korea (the Republic of)
Background

NLRP3 inflammasome is a multiprotein oligomer that promotes the maturation of IL-1β and IL-18. NFAT5 is an essential transcription factor regulating cellular homeostasis to hypertonicity-induced osmotic stress, and recently reported as pro-inflammatory and pro-fibrotic mediator. We investigated whether NFAT5 played a role in peritoneal fibrosis and epithelial-to-mesenchymal transition (EMT) via a modulation of NLRP3 inflammasome

Methods

The expressions of NFAT5 and components of NLRP3 inflammasome (NLRP3, ASC, and procaspase-1) were evaluated in human peritoneal mesothelial cells (HPMCs) and animal model of peritoneal fibrosis. Effects of siNFAT5, siNLRP3, siASC or NLRP3 inflammasome inhibitor (MCC950) on EMT of HPMCs were evaluated. Peritoneal EMT and fibrosis were compared in adenoviral vector of TGFβ (ad-TGFβ)-injected NFAT5 +/+ and +/- mice

Results

TGFβ increased NFAT5 expression and its nuclear translocation in HPMCs. TGFβ-induced EMT was associated with an up-regulation of NLRP3, ASC, procaspase-1 and an increased production of IL-1β/IL-18. siNFAT5 ameliorated TGFβ-induced NLRP3 inflammasome pathway and EMT with an increase in E-cadherin promotor activity as well as a decrease in snail expression and nuclear translocation of β-catenin. siNLRP3, siASC, and MCC950 also alleviated TGFβ-induced EMT. In NFAT5+/- mice, ad-TGFβ induced peritoneal fibrosis were ameliorated with a reduction in peritoneal thickness compared to wild-type NFAT5 +/+ mice

Conclusion

This data suggest NFAT5 plays a key role in peritoneal fibrosis via tonicity-independent mechanism by either an inhibition of E-cadherin transcription and activation of NLRP3 inflammasome. Modulation of NFAT5 and NLRP3 inflammasome in peritoneum could be a novel approach to protect peritoneal fibrosis in PD patients