Astragalus Inhibits Epithelial-to-Mesenchymal Transition of Peritoneal Mesothelial Cells by Down-Regulating β-Catenin

Abstract

Background/Aims: The epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) is a crucial event in the induction of peritoneal fibrosis (PF), in which canonical Wnt/β-catenin signaling participates. Smads signaling is reported to interact with β-catenin and synergistically regulates EMT. This study was aimed to reveal the effect of Astragalus on β-catenin in EMT of PMCs. Methods: To obtain the role of β-catenin in EMT, gene transfer into HMrSV5 cell line and rats has been achieved. After Astragalus treatment, EMT markers and signaling pathway-related indicators were detected by western blotting, immunofluorescence, immunohistochemistry, immunoprecipitation and real time-PCR. Results: β-catenin knockdown suppressed EMT of HMrSV5 cells. Astragalus alleviated EMT of PMCs characterized by increased E-cadherin and decreased α-SMA and Vimentin. In rat model of peritoneal dialysis (PD), Astragalus attenuated peritoneal thickening and fibrosis. Astragalus down-regulated β-catenin by stabilizing the Glycogen synthase kinase-3β (GSK-3β)/β-catenin complex and further inhibited the nuclear translocation of β-catenin. Meanwhile, Astragalus down-regulated β-catenin by enhancing Smad7 expression. Silencing Smad7 antagonized the EMT-inhibitory effect of Astragalus. Conclusion: Astragalus inhibits EMT of PMCs by down-regulating β-catenin. The modulation of β-catenin in peritoneum can be a novel tool to prevent PF.

Ginsenoside Rg3 Reduces Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β1 by Inactivation of AKT in HMrSV5 Peritoneal Mesothelial Cells

“…Long-term peritoneal dialysis results in peritoneal fibrosis, and there is a lack of an appropriate therapeutic strategy for the prevention of peritoneal fibrosis to improve the prognosis of end-stage renal disease (ESRD). Previous reports have shown that some compounds [15,17] and herbal medicines [18] are effective in the treatment of human peritoneal cells in vitro and in vivo . The capacity of ginsenoside Rg3 to prevent mesothelial cell epithelial-mesenchymal transition (EMT) has been observed in previous studies.…”

“…The present study was the first to report that ginsenoside Rg3 also could reverse TGF-β1-induced EMT in human peritoneal cells. Although the herbal medicine astragaloside IV also reversed the TGF-β1-induced EMT in human peritoneal cells, its effective dose (400 μg/mL) [18] was significantly higher than that of ginsenoside Rg3 (2 μg/mL), suggesting improved pharmacological activity of ginsenoside Rg3. The antiproliferation activity of ginsenoside Rg3 has been reported in several types of cancer cells [13].…”

“…Recently published studies have shown that some non-Smad signaling pathways also contribute to TGF-β-induced EMT [15,18]. A previous study showed that the TβRI can directly bind to PI3K with the induction of TGF-β1, leading to the activation of the PI3K/AKT pathway [22].…”

Loosening of the mesothelial barrier as an early therapeutic target to preserve peritoneal function in peritoneal dialysis

“…Based on experimental data using TGF-β1, the most potent pro-fibrotic cytokine known to induce EMT, the balance among Smad2, Smad3, and Smad7 plays a role in the development of EMT of MCs [34]. Smad proteins, phosphorylated by TGF-β1 stimulation, control transcription of TGF-β1 responsive genes [34,35], many of which are identified as pro-fibrogenic genes and regulators of EMT in peritoneal fibrosis, including Snail [36,37], fibronectin [38,39], connective tissue growth factor [40], β-catenin [41], monocyte chemoattractant protein-1 [42], and matrix metalloproteinase-2 [43,44]. Therefore, TGF-β1-induced mesothelial transition leads to a characteristic myofibroblastic phenotype and complex modulation of gene expression, including cytoskeletal organization, cell adhesion, and ECM production [8,45].…”

Effect of astragaloside IV and the role of nuclear receptor RXRα in human peritoneal mesothelial cells in high glucose‑based peritoneal dialysis fluids

“…Previous studies have shown that Astragalus membranaceus inhibits peritoneal fibrosis in PD through monocyte chemoattractant protein-1 and the TGF-β1 pathway (25), and ameliorates renal interstitial fibrosis by inhibiting EMT, inflammation, TLR4/NF-κB and cyrillic B (25)(26)(27). Astragalus inhibits PMC EMT by downregulating β-catenin (28). Astragaloside IV is a key compound extracted from Astragalus membranaceus (27,29,30).…”