Article ; Online: Astragaloside IV inhibits glucose-induced epithelial-mesenchymal transition of podocytes through autophagy enhancement via the SIRT-NF-κB p65 axis.
2019 Volume 9, Issue 1, Page(s) 323
Abstract: Both autophagy and podocyte epithelial-mesenchymal transition (EMT) are critical factors in glomerular diseases that involve proteinuria and fibrosis. Here, we sought to determine whether plant-derived saponin astragaloside IV (AS-IV) was able to reverse ...
| Abstract | Both autophagy and podocyte epithelial-mesenchymal transition (EMT) are critical factors in glomerular diseases that involve proteinuria and fibrosis. Here, we sought to determine whether plant-derived saponin astragaloside IV (AS-IV) was able to reverse renal fibrosis and improve renal function through regulation of autophagy and podocyte EMT. Cultured immortalized mouse podocytes and KK-Ay mice models of diabetes were exposed to AS-IV. Western blotting, real-time PCR, immunofluorescence and histochemistry were used to analyze markers of autophagy and podocyte EMT. We observed that AS-IV inhibited glucose-induced podocyte EMT and enhanced autophagy by decreasing NF-κB subunit p65 acetylation as well as increasing Sirtuin1 (SIRT1) expression. Treatment of the cells and animal models with a SIRT1 inhibitor EX527 was able to reverse these effects. The SIRT1 activator SRT1720 was also found to decrease p65 acetylation and enhance autophagy in glucose-induced podocyte EMT. Additionally, further treatment with autophagy inhibitor 3-methyladenine was able to reverse the effects of AS-IV on podocyte EMT, while the autophagy activator rapamycin or the NF-κB pathway inhibitor ammonium pyrrolidinedithiocarbamate (PDTC) were able to reverse glucose-induced podocyte EMT. Notably, both renal fibrosis and renal function in diabetic KK-Ay mice were improved after treatment with AS-IV. These findings support AS-IV as a renoprotective agent that likely exerts its effects on podocyte EMT through modulation of the SIRT1-NF-κB pathway and autophagy activation. Further studies are required to clarify the role of AS-IV as a potential therapeutic agent in glomerular diseases. |
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| MeSH term(s) | Animals ; Autophagy ; Cell Line ; Diabetic Nephropathies/drug therapy ; Disease Models, Animal ; Epithelial-Mesenchymal Transition/drug effects ; Glucose/metabolism ; Kidney Function Tests ; Mice ; Models, Biological ; Podocytes/drug effects ; Saponins/metabolism ; Sirtuin 1/metabolism ; Transcription Factor RelA/metabolism ; Treatment Outcome ; Triterpenes/metabolism |
| Chemical Substances | Rela protein, mouse ; Saponins ; Transcription Factor RelA ; Triterpenes ; astragaloside A (3A592W8XKE) ; Sirt1 protein, mouse (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-) ; Glucose (IY9XDZ35W2) |
| Language | English |
| Publishing date | 2019-01-23 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2615211-3 |
| ISSN | 2045-2322 ; 2045-2322 |
| ISSN (online) | 2045-2322 |
| ISSN | 2045-2322 |
| DOI | 10.1038/s41598-018-36911-1 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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