Astragaloside IV Blunts Epithelial-Mesenchymal Transition and G2/M Arrest to Alleviate Renal Fibrosis via Regulating ALDH2-Mediated Autophagy.

Abstract

Previous studies show that astragaloside IV (ASIV) has anti-renal fibrosis effects. However, its mechanism remains elusive. In this study, we investigated the anti-fibrosis mechanisms of ASIV on chronic kidney disease (CKD) in vivo and in vitro. A CKD model was induced in rats with adenine (200 mg/kg/d, i.g.), and an in vitro renal fibrosis model was induced in human kidney-2 (HK-2) cells treated with TGF-β1. We revealed that ASIV significantly alleviated renal fibrosis by suppressing the expressions of epithelial-mesenchymal transition (EMT)-related proteins, including fibronectin, vimentin, and alpha-smooth muscle actin (α-SMA), and G2/M arrest-related proteins, including phosphorylated p53 (p-p53), p21, phosphorylated histone H3 (p-H3), and Ki67 in both of the in vivo and in vitro models. Transcriptomic analysis and subsequent validation showed that ASIV rescued ALDH2 expression and inhibited AKT/mTOR-mediated autophagy. Furthermore, in ALDH2-knockdown HK-2 cells, ASIV failed to inhibit AKT/mTOR-mediated autophagy and could not blunt EMT and G2/M arrest. In addition, we further demonstrated that rapamycin, an autophagy inducer, reversed the treatment of ASIV by promoting autophagy in TGF-β1-treated HK-2 cells. A dual-luciferase report assay indicated that ASIV enhanced the transcriptional activity of the ALDH2 promoter. In addition, a further molecular docking analysis showed the potential interaction of ALDH2 and ASIV. Collectively, our data indicate that ALDH2-mediated autophagy may be a novel target in treating renal fibrosis in CKD models, and ASIV may be an effective targeted drug for ALDH2, which illuminate a new insight into the treatment of renal fibrosis and provide new evidence of pharmacology to elucidate the anti-fibrosis mechanism of ASIV in treating renal fibrosis.

• Authors: Dong Li, Yuzhe Liu, Quancao Zhan, Yan Zeng, Ze Peng, Qifeng He, Qi Tan, Wenfu Cao, Shang Wang, Jianwei Wang
• Journal: Cells (Cells) Vol. 12 Issue 13 (Jul 04 2023) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 37443810 (Publication Type: Journal Article)

Chemical References

• Transforming Growth Factor beta1
• astragaloside A
• Proto-Oncogene Proteins c-akt
• Tumor Suppressor Protein p53
• TOR Serine-Threonine Kinases
• ALDH2 protein, human
• Aldehyde Dehydrogenase, Mitochondrial

Topics

• Rats
• Humans
• Animals
• Transforming Growth Factor beta1 (metabolism)
• Epithelial-Mesenchymal Transition
• Proto-Oncogene Proteins c-akt (metabolism)
• Apoptosis
• Molecular Docking Simulation
• Tumor Suppressor Protein p53
• Cell Line, Tumor
• G2 Phase Cell Cycle Checkpoints
• Fibrosis
• Renal Insufficiency, Chronic
• TOR Serine-Threonine Kinases (metabolism)
• Autophagy
• Aldehyde Dehydrogenase, Mitochondrial (metabolism)