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Kidney Week

Abstract: SA-PO682

PPARα Modulator Ameliorates Methylglyoxal-Induced Peritoneal Fibrosis

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

  • Shinkai, Yutaka, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan
  • Tamura, Ryo, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan
  • Ishiuchi, Naoki, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan
  • Osaki, Yosuke, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan
  • Maeoka, Yujiro, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan
  • Sasaki, Kensuke, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan
  • Masaki, Takao, Hiroshima Daigaku Daigakuin Ikei Kagaku Kenkyuka, Hiroshima, Hiroshima, Japan
Background

Peritoneal inflammation and fibrosis remain major obstacles to the long-term maintenance of peritoneal dialysis. In this study, we investigated whether PPARα agonism ameliorates peritoneal inflammation and fibrosis in methylglyoxal (MGO) induced peritoneal injury in mice, as well as in cultured human peritoneal mesothelial cells (HPMCs) and THP-1 cells.

Methods

Peritoneal fibrosis was induced by intraperitoneal injection of MGO in male C57/B6 mice for 3 weeks. The mice were fed normal chow diet with a specific PPARα modulator, pemafibtare (0.3 mg/kg), 3 weeks before MGO injection, and then peritoneal tissues were examined. In vitro study, HPMC and THP-1 cells stimulated with IFN-γ were examined with or without pemafibrate treatment.

Results

Pemafibrate increased PPARα expression in the peritoneum. Pemafibrate significantly decreased MGO-induced cell density and peritoneal thickening. In immunohistochemical staining, pemafibrate reduced the number of fibrosis markers α-SMA, TGF-β1, and FSP-1 positive cells and deposition of collagen I and III, the expression of the inflammatory cytokine TNF-α, and macrophage infiltration. In addition, pemafibrate improved the deterioration of the dialysate-to-plasma (D/P) ratio of BUN and glucose and reduced TGF-β1 expression in the dialysate. In vitro studies, pemafibrate inhibited IFN-γ-induced activation of fibrosis markers (TGF-β1, fibronectin) in HPMC. In THP-1 cells, pemafibrate promoted anti-inflammatory M2 macrophage polarity and inhibited inflammatory M1 macrophage cytokine production, including IL-1β. Moreover, Pemafibrate suppressed not only AP-1 signaling pathway but also NLRP3 inflammasome and caspase-1 activation in HPMC.

Conclusion

The specific PPARα modulator, Pemafibrate ameliorates peritoneal fibrosis by inhibiting peritoneal inflammation.