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Abstract: SA-PO677

Matrix Metalloproteinase-10 Deficiency Has Protective Effects Against Peritoneal Inflammation and Fibrosis via NFκΒ Pathway Inhibition

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

  • Yokoi, Hideki, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
  • Ishimura, Takuya, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
  • Ishii, Akira, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
  • Yamada, Hiroyuki, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
  • Toda, Naohiro, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
  • Mori, Keita P., Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  • Ohno, Shoko, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
  • Kato, Yukiko, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
  • Handa, Takaya, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  • Ikushima, Akie, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
  • Sugioka, Sayaka, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
  • Nishio, Haruomi, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
  • Yanagita, Motoko, Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
Background

One of the most common causes of discontinuation of peritoneal dialysis is impaired peritoneal function. However, its molecular mechanisms remain unclear. We have previously demonstrated that MMP (matrix metalloproteinase)-10 gene expression is significantly increased by microarray analysis of peritoneal fibrosis mice, but its function has not been elucidated yet.

Methods

Chlorhexidine gluconate (CG) was intraperitoneally injected to wild-type and MMP-10 knockout mice to elucidate the role of MMP-10 on peritoneal injury. We also examined function of peritoneal macrophages and mesothelial cells obtained from wild-type and MMP-10 knockout mice, and human MMP-10-overexpressing RAW 264.7 cells and MeT-5A cells. In addition, we investigated MMP-10 expression on human peritoneal biopsy specimen, and association between serum proMMP-10 and peritoneal permeability determined by peritoneal equilibration test (PET).

Results

MMP-10 was expressed in positive cells for WT1, a mesothelial marker, and also for MAC-2, a macrophage marker, in the thickened peritoneum of both mice and humans. Serum proMMP-10 levels were well correlated with peritoneal permeability indicated by D/P Cr. Peritoneal fibrosis, inflammation, and high peritoneal permeability induced by CG were all ameliorated by MMP-10 deletion, with reduction of CD31-positive vessels and VEGF-A-positive cells. Expression of Ccl2, Tnfa, and Il6 and phosphorylation of NFκΒ subunit p65 at S536 were suppressed in both MMP-10 knockout macrophages and mesothelial cells in response to lipopolysaccharide (LPS) stimulation. Overexpression of MMP-10 in RAW 264.7 and MeT-5A cells upregulated mRNA expression of pro-inflammatory cytokines with phosphorylation of NFκΒ subunit p65.

Conclusion

Inflammatory responses induced by MMP-10 are mediated through NFκΒ pathway, and that systemic deletion of MMP-10 ameliorates peritoneal inflammation and fibrosis caused by MMP-10-induced NFκΒ activation of peritoneal macrophages and mesothelial cells.

Funding

  • Private Foundation Support