Abstract: TH-PO843

Inhibition of H3K4 Methyltransferase SET7/9 Ameliorates Peritoneal Fibrosis

Session Information

  • Peritoneal Dialysis - I
    November 02, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Dialysis

  • 608 Peritoneal Dialysis

Authors

  • Tamura, Ryo, Hiroshima University Hospital, Hiroshima, Japan
  • Doi, Shigehiro, Hiroshima University Hospital, Hiroshima, Japan
  • Nakashima, Ayumu, Hiroshima University Hospital, Hiroshima, Japan
  • Sasaki, Kensuke, Hiroshima University Hospital, Hiroshima, Japan
  • Ueno, Toshinori, Hiroshima University Hospital, Hiroshima, Japan
  • Masaki, Takao, Hiroshima University Hospital, Hiroshima, Japan
Background

Transforming growth factor-β1 (TGF-β1) is widely recognized as a major mediator of peritoneal fibrosis. TGF-β1 is reportedly responsible for the expression of the H3K4 methyltransferase, SET7/9. SET7/9-induced H3K4 monomethylation (H3K4me1) has a critical function in transcriptional activation of fibrotic genes. In this study, we examined the inhibitory effects of SET7/9 on peritoneal fibrosis in mice and human peritoneal mesothelial cells (HPMCs). We also investigated SET7/9 expression in nonadherent cells isolated from peritoneal dialysis (PD) effluent from actual PD patients.

Methods

Peritoneal fibrosis was induced by intraperitoneal injection of methylglyoxal (MGO) in male C57/B6 mice for 21 days. Sinefungin, a SET7/9 inhibitor, was administered subcutaneously just before MGO injections at 10 mg/kg. In in vitro experiments, HPMCs were pre-incubated with 3 or 10 µL/mL sinefungin 1 hour before stimulation with 5 ng/ml of TGF-β1.

Results

SET7/9 expression increased in both MGO-injected mice and nonadherent cells isolated from effluent of PD patients, and was positively correlated with dialysate-to-plasma ratio of creatinine. Immunohistochemical staining showed that sinefungin suppressed expression of mesenchymal cells and collagen deposition, which was accompanied by decreased H3K4me1 expression. A peritoneal equilibration test showed that sinefungin attenuated the transport rate of blood urea nitrogen from plasma and the absorption rate of glucose from dialysate. In in vitro experiments, sinefungin suppressed TGF-β1-induced expression of fibrotic markers while inhibiting H3K4me1.

Conclusion

These findings suggest that inhibition of H3K4 methyltransferase SET7/9 ameliorates peritoneal fibrosis by inhibiting H3K4me1.