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Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice
Jin Sug Kim1, Kyung Sook Cho1, Seon Hwa Park2
1Division of Nephrology, Department of Internal Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul, Republic of Korea.
Background:
Peritoneal fibrosis is a devastating complication of peritoneal dialysis. However, its precise mechanism is unclear, and specific treatments have not yet been established. Recent evidence suggests that the sonic hedgehog (SHH) signaling pathway is involved in tissue fibrogenesis. Drugs that inhibit this pathway are emerging in the field of anti-fibrosis therapy. Itraconazole, an anti-fungal agent, was also recently recognized as an inhibitor of the SHH signaling pathway. In this study, we used a mouse model to investigate whether the SHH signaling pathway is involved in the development of peritoneal fibrosis and the effects of itraconazole on peritoneal fibrosis.
Methods:
Peritoneal fibrosis was induced by intraperitoneal (IP) injection of 0.1% chlorhexidine gluconate (CG) solution every other day for 4 weeks, with or without itraconazole treatment (20 mg/kg, IP injection on a daily basis). Male C57BL/6 mice were divided into 4 groups: saline group, saline plus itraconazole group, CG group, and CG plus itraconazole group. Isotonic saline was administered intraperitoneally to the control group. The peritoneal tissues were evaluated for histological changes, expression of fibrosis markers, and the main components of the SHH signaling pathway.
Results:
Peritoneal thickening was evident in the CG group and was significantly decreased by itraconazole administration (80.4 ± 7.7 vs. 28.2 ± 3.8 µm, p < 0.001). The expression of the following SHH signaling pathway components was upregulated in the CG group and suppressed by itraconazole treatment: SHH, patched, smoothened, and glioma-associated oncogene transcription factor 1. The IP injection of CG solution increased the expression of fibrosis markers such as α-smooth muscle actin and transforming growth factor-β1 in the peritoneal tissues. Itraconazole treatment significantly decreased the expression of these markers.
Conclusion:
Our study provides the first evidence that the SHH signaling pathway may be implicated in peritoneal fibrosis. It also demonstrates that itraconazole treatment has protective effects on peritoneal fibrosis through the regulation of the SHH signaling pathway. These findings suggest that blockage of the SHH signaling pathway is a potential therapeutic strategy for peritoneal fibrosis.
Insights
Itraconazole, an antifungal drug, effectively treats peritoneal fibrosis in mice by inhibiting the Sonic Hedgehog (SHH) signaling pathway. This study reveals SHH pathway
Area of Science:
- Nephrology
- Gastroenterology
- Pharmacology
Background:
- Peritoneal fibrosis is a serious complication of peritoneal dialysis with unclear mechanisms and no established treatments.
- The Sonic Hedgehog (SHH) signaling pathway is implicated in fibrogenesis, and its inhibitors are being explored for anti-fibrosis therapies.
- Itraconazole, an antifungal agent, has been identified as an inhibitor of the SHH signaling pathway.
Purpose of the Study:
- To investigate the role of the SHH signaling pathway in the development of peritoneal fibrosis.
- To evaluate the therapeutic effects of itraconazole on peritoneal fibrosis in a mouse model.
- To determine if itraconazole exerts its effects by regulating the SHH signaling pathway.
Main Methods:
- Peritoneal fibrosis was induced in mice using intraperitoneal injections of chlorhexidine gluconate (CG) solution.
- Mice received daily intraperitoneal injections of itraconazole (20 mg/kg) or saline.
- Histological analysis, fibrosis marker expression, and SHH signaling pathway component analysis were performed on peritoneal tissues.
Main Results:
- CG-induced peritoneal thickening was significantly reduced by itraconazole treatment (80.4 ± 7.7 µm to 28.2 ± 3.8 µm).
- Expression of SHH pathway components (SHH, patched, smoothened, GLI1) was upregulated by CG and suppressed by itraconazole.
- Itraconazole treatment significantly decreased the expression of fibrosis markers alpha-smooth muscle actin and transforming growth factor-beta1.
Conclusions:
- This study provides the first evidence implicating the SHH signaling pathway in peritoneal fibrosis.
- Itraconazole demonstrates protective effects against peritoneal fibrosis by modulating the SHH signaling pathway.
- Inhibition of the SHH signaling pathway represents a potential therapeutic strategy for peritoneal fibrosis.
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