Abstract: TH-PO852

Itraconazole Ameliorates Chlorhexidine Gluconate-Induced Peritoneal Fibrosis in Mice through Regulating Hedgehog Signaling Pathway

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

  • Kim, Jin sug, Kyung Hee University Medical Center, Seoul, Korea (the Republic of)
  • Jeong, Kyung-hwan, Kyung Hee University Medical Center, Seoul, Korea (the Republic of)
  • Lee, Yu ho, Kyung Hee University Hospital at Gangdong, Seoul, Korea, Seoul, Korea (the Republic of)
  • Park, Eun ji, Kyung Hee University Medical Center, Seoul, Korea (the Republic of)
  • Jung, Su Woong, Kyung Hee University Medical Center, Seoul, Korea (the Republic of)
  • Ihm, Chun-Gyoo, Kyung Hee University Medical Center, Seoul, Korea (the Republic of)
  • Lee, Tae won, Kyung Hee University Medical Center, Seoul, Korea (the Republic of)
  • Kim, Yang gyun, Kyung Hee University Hospital at Gangdong, Seoul, Korea, Seoul, Korea (the Republic of)
  • Moon, Ju young, Kyung Hee University Hospital at Gangdong, Seoul, Korea, Seoul, Korea (the Republic of)
  • Lee, Sang-Ho, Kyung Hee University Hospital at Gangdong, Seoul, Korea, Seoul, Korea (the Republic of)
Background

Peritoneal fibrosis is a devastating complication of peritoneal dialysis (PD). However, the precise mechanism is unclear and specific treatment has not yet been established. Recent evidence suggests that Sonic hedgehog (Shh) signaling pathway is involved in fibrogenesis, and drugs that inhibit this pathway are emerging in the treatment of fibrosis. Itraconazole, an anti-fungal agent, is recently also reported as an inhibitor of Shh signaling pathway. In this study, we investigated whether itraconazole suppressed chlorhexidine gluconate (CG)-induced peritoneal fibrosis in mice.

Methods

Peritoneal fibrosis was induced by intraperitoneal (IP) injection of 0.1% CG every other day for 4 weeks, with or without itraconazole treatment (20mg/kg, IP injection on a daily basis). Saline was administered intraperitoneally to the control groups. Male C57BL/6 mice were divided into four groups: saline injection (group 1), saline injection plus itraconazole (group 2), CG injection (group 3), CG injection plus itraconazole (group 4). The effects of itraconazole were evaluated based on peritoneal thickness, immunohistochemical staining, and real-time polymerase chain reaction. The peritoneal thickness was identified by Masson’s trichrome staining.

Results

Peritoneal thickening was evident in group 3 (CG injection), and the thickening was markedly decreased in group 4 (CG injection plus itraconazole) (59.9±34.9 µm vs. 16.8±9.0 µm, p<0.001). The mRNA expression of markers for fibrosis, including transforming growth factor-β1 (TGF-β1), fibronectin, and α-smooth muscle actin (α-SMA), were increased in the group 3 and were downregulated in the group 4. Similar results were shown in the markers for Shh signaling pathway. Itraconazole suppressed mRNA expression of Shh, Patched 1 (PTCH1), Smoothened (SMO), and Gli in peritoneal tissues. Immunohistochemistry analysis revealed that the expression of Hedgehog pathway components were increased in group 3, and decreased by using Itraconaozle in peritoneal tissues.

Conclusion

Our results suggest that itraconazole ameliorates the peritoneal fibrosis by regulating Shh signaling pathway. Itraconazole can be a potential therapeutic strategy for peritoneal fibrosis.