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Abstract: SA-PO943

Crucial Role of NLRP3 Inflammasome in the Development of Peritoneal Dialysis-Related Peritoneal Fibrosis

Session Information

Category: Dialysis

  • 703 Dialysis: Peritoneal Dialysis

Authors

  • Hishida, Erika, Jichi Medical University, Yakushiji, Shimotsuke-shi, Tochigi, Japan
  • Komada, Takanori, Jichi Medical University, Yakushiji, Shimotsuke-shi, Tochigi, Japan
  • Akimoto, Tetsu, Jichi Medical University, Yakushiji, Shimotsuke-shi, Tochigi, Japan
  • Takahashi, Masafumi, Jichi Medical University, Yakushiji, Shimotsuke-shi, Tochigi, Japan
  • Nagata, Daisuke, Jichi Medical University, Yakushiji, Shimotsuke-shi, Tochigi, Japan
Background

Long-term peritoneal dialysis (PD) therapy leads to peritoneal inflammation and fibrosis. However, the mechanism underlying PD-related peritoneal inflammation and fibrosis remains unclear. Recent evidence indicates that sterile inflammation triggered by danger signals is mediated through a multiprotein complex called the NLRP3 inflammasome. In the present study, we investigated the role of NLRP3 inflammasome in the pathophysiology of peritoneal fibrosis using a mouse model of methylglyoxal (MGO)-induced PF.

Methods

C57BL/6J (wild-type [WT]) and ASC-deficient mice were mainly used throughout the study. PF was induced by intraperitoneal injection of peritoneal dialysis fluid (PDF) (100 mL/kg) containing 40 mM MGO solution for 3 weeks, 5 consecutive days per week. The control group received the same volume of PDF.In in vitro experiments, human umbilical vein endothelial cells (HUVEC) and primary mouse lung vascular endothelial cells (MLVEC), were stimulated with MGO.

Results

Inflammasome-related molecules were upregulated in the peritoneum of MGO-treated mice. MGO induced parietal and visceral peritoneal fibrosis in wild-type mice, which was significantly attenuated in mice deficient in NLRP3, ASC and interleukin-1β. ASC deficiency reduced the expression of inflammatory cytokines and fibrotic factors, and the infiltration of macrophages. However, myeloid cell-specific ASC deficiency (ASCf/f; LysMcre/+) failed to inhibit MGO-induced peritoneal fibrosis. MGO caused hemorrhagic ascites, fibrin deposition, and plasminogen activator inhibitor-1 upregulation, but all of these manifestations were inhibited by ASC deficiency. Furthermore, in vitro experiments showed that MGO induced cell death via the generation of reactive oxygen species in vascular endothelial cells, which was inhibited by ASC deficiency.

Conclusion

Our results showed that endothelial NLRP3 inflammasome contributes to
PD-related peritoneal inflammation and fibrosis, and provide new insights into the mechanisms underlying the pathogenesis of this disorder.

Funding

  • Commercial Support