Astragaloside IV Alleviates Intestinal Barrier Dysfunction via the AKT-GSK3β-β-Catenin Pathway in Peritoneal Dialysis

Abstract

Background and aims: Long-term peritoneal dialysis (PD) causes intestinal dysfunction, including constipation, diarrhea, or enteric peritonitis. However, the etiology and pathogenesis of these complications are still unclear and there are no specific drugs available in the clinic. This study aims to determine whether Astragaloside IV (AS IV) has therapeutic value on PD-induced intestinal epithelial barrier dysfunction in vivo and in vitro.Methods: We established two different long-term PD treatment mice models by intraperitoneally injecting 4.25% dextrose-containing peritoneal dialysis fluid (PDF) in uremia mice and normal mice, which were served as controls. In addition, PDF was applied to T84 cells in vitro. The therapeutic effects of AS IV on PD-induced intestinal dysfunction were then examined by histopathological staining, transmission electron microscopy, western blotting, and reverse transcription polymerase chain reaction. The protein levels of protein kinase B (AKT), glycogen synthase kinase 3β (GSK-3β) and β-catenin were examined after administration of AS IV.Results: In the present study, AS IV maintained the intestinal crypt, microvilli and desmosome structures in an orderly arrangement and improved intestinal epithelial permeability with the up-regulation of tight junction proteins in vivo. Furthermore, AS IV protected T84 cells from PD-induced damage by improving cell viability, promoting wound healing, and increasing the expression of tight junction proteins. Additionally, AS IV treatment significantly increased the levels of phosphorylation of AKT, inhibited the activity GSK-3β, and ultimately resulted in the nuclear translocation and accumulation of β-catenin.Conclusion: These findings provide novel insight into the AS IV-mediated protection of the intestinal epithelial barrier from damage via the AKT-GSK3β-β-catenin signal axis during peritoneal dialysis.

Scaffold Adhering to Peptide-Based Biomimetic Extracellular Matrix Composite Nanobioglass Promotes the Proliferation and Migration of Skin Fibroblasts Through the GSK-3β/β-Catenin Signaling Axis

“…41 However, since GSK-3β was a hub gene of other signaling pathways such as PI3K/Akt, NOTCH, and so on, 42,43 there would be some crosstalk between these pathways, resulting in similar trends in the expression levels of GSK-3β as β-catenin and p-GSK-3β. [44][45][46] This suggested that when the Wnt signaling pathway was unobstructed, BM could activate Wnt to promote wound healing. Conversely, when Wnt was blocked, the potential role of BM in proliferation was significantly reduced.…”

Advances in stem cell therapy for peritoneal fibrosis: from mechanisms to therapeutics

“…Notably, traditional Chinese medicine (TCM) offers a unique approach to the treatment of complex chronic diseases. It has been shown that TCMs such as astragalus, rhubarb, safflower and curcumin exert significant therapeutic effects on peritoneal injury as well as regulating inflammation and inhibiting abnormal ECM accumulation [123][124][125][126]. And SCs pretreated with TCMs have been proven to play a therapeutic role in many diseases [127,128].…”

Blockade of PI3K/AKT signaling pathway by Astragaloside IV attenuates ulcerative colitis via improving the intestinal epithelial barrier

“…AS-IV prevents tight junctions (TJs) disruption and intestinal barrier damage by inhibiting activation of RhoA/NLRP3 inflammatory vesicle signaling in an in vivo cecal ligation and puncture (CLP)-induced sepsis model and an in vitro Lipopolysaccharide (LPS)-primed Caco-2 monolayer barrier model [ 27 ]. AS-IV promotes the phosphorylation level of AKT, inhibits GSK-3β activity, leads to nuclear translocation and accumulation of β-catenin, improves cell viability, and promotes the expression of TJ proteins and wound healing to alleviate Peritoneal Dialysis (PD)-associated intestinal dysfunction [ 28 ]. Given that AS-IV plays an important role in the repair of barrier function in vivo, we sought to explore the potential impact of the administration of AS-IV on barrier function in dextran sodium sulfate (DSS)-induced colitis mice, and whether PI3K/AKT plays a role in it.…”