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Asiaticoside protects against PDF-induced peritoneal fibrosis via suppression of AhR/Nrf2-mediated MMT and oxidative
Junyi Zhao1,2, Wen Zhou3, Wenxuan Xue1,2
1Institute of Literature in Chinese Medicine, Nanjing University of Chinese Medicine, No. 138, Xianlin Avenue, Nanjing City, Jiangsu Province, China.
Abstract:
Peritoneal fibrosis (PF) is a major complication of long-term peritoneal dialysis (PD). This study investigated the protective effects and mechanisms of asiaticoside (AC) against PF. In vitro, HMrSV5 cells were exposed to peritoneal dialysis fluid (PDF) with or without AC, and assessed for viability, migration, fibrosis/mesothelial-to-mesenchymal transition (MMT) markers (α-smooth muscle actin (α-SMA), Collagen I, E-cadherin, Vimentin), reactive oxygen species (ROS), mitochondrial membrane potential, and aryl hydrocarbon receptor (AhR) transcriptional activity using a dual-luciferase reporter assay. Subcellular localization of AhR was evaluated to examine nuclear translocation, and AhR overexpression was employed to confirm pathway dependence and its interaction with nuclear factor erythroid 2 related factor 2 (Nrf2). In vivo, mice received daily intraperitoneal 4.25% PDF with or without oral AC (50 or 100 mg/kg), and peritoneal function, histology, and α-SMA/Collagen I expression were quantified. AC co-treatment significantly inhibited PDF-induced MMT, oxidative stress, mitochondrial dysfunction, and AhR nuclear translocation, while enhancing Nrf2 nuclear accumulation; AhR overexpression partially reversed these effects. In mice, AC preserved peritoneal function, reduced fibrosis, and modulated AhR-Nrf2 signaling. These results demonstrate that AC protects against PDF-induced PF by suppressing AhR activation and promoting Nrf2 nuclear translocation, indicating its protective effects in preclinical models of PD-associated PF.
Insights
Asiaticoside (AC) protects against peritoneal fibrosis (PF) in peritoneal dialysis (PD) patients. This compound inhibits oxidative stress and modulates key signaling pathways, offering a potential therapeutic strategy for PD-associated complications.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Peritoneal fibrosis (PF) is a serious complication of long-term peritoneal dialysis (PD).
- Understanding the molecular mechanisms underlying PF is crucial for developing effective treatments.
- The aryl hydrocarbon receptor (AhR) pathway is implicated in PF pathogenesis.
Purpose of the Study:
- To investigate the protective effects of asiaticoside (AC) against peritoneal fibrosis induced by peritoneal dialysis fluid (PDF).
- To elucidate the underlying mechanisms involving AhR and Nrf2 signaling pathways.
- To evaluate AC's efficacy in both in vitro and in vivo models of PD-associated PF.
Main Methods:
- In vitro studies using HMrSV5 cells exposed to PDF with/without AC, assessing cell viability, migration, fibrosis markers (α-SMA, Collagen I), oxidative stress (ROS), mitochondrial potential, and AhR activity.
- In vivo studies using mice treated with PDF and AC, evaluating peritoneal function, histology, and fibrotic markers.
- Analysis of AhR and Nrf2 nuclear translocation and interaction.
Main Results:
- AC significantly inhibited PDF-induced mesothelial-to-mesenchymal transition (MMT), oxidative stress, and mitochondrial dysfunction in vitro.
- AC suppressed PDF-induced AhR nuclear translocation and promoted Nrf2 nuclear accumulation.
- In vivo, AC preserved peritoneal function, reduced fibrosis, and modulated AhR-Nrf2 signaling.
Conclusions:
- Asiaticoside (AC) demonstrates significant protective effects against peritoneal fibrosis in preclinical models of peritoneal dialysis (PD).
- AC functions by suppressing aryl hydrocarbon receptor (AhR) activation and promoting nuclear factor erythroid 2 related factor 2 (Nrf2) translocation.
- AC represents a promising therapeutic candidate for managing PD-associated peritoneal fibrosis.