Saikosaponin B2 attenuates kidney fibrosis via inhibiting the Hedgehog Pathway
| Autor: | Jiahong Yang, Dadui Ren, Xuemei Zhang, Jing Zhang, Hong Xin, Nengneng Cheng, Yingxue Li, Junqiu Liu, Jia Luo |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Pharmaceutical Science Zinc Finger Protein Gli2 Kidney Mice 03 medical and health sciences 0302 clinical medicine GLI1 Drug Discovery Renal fibrosis Animals Humans Hedgehog Proteins Oleanolic Acid Sonic hedgehog Hedgehog 030304 developmental biology Pharmacology 0303 health sciences biology Chemistry NF-kappa B Wnt signaling pathway Fibroblasts Saponins Fibrosis Smoothened Receptor Hedgehog signaling pathway Rats Mice Inbred C57BL HEK293 Cells Complementary and alternative medicine 030220 oncology & carcinogenesis NIH 3T3 Cells Cancer research biology.protein Molecular Medicine Kidney Diseases Signal transduction Signal Transduction |
| Zdroj: | Phytomedicine. 67:153163 |
| ISSN: | 0944-7113 |
| DOI: | 10.1016/j.phymed.2019.153163 |
| Popis: | Background Renal interstitial fibrosis is a common pathway through which chronic kidney disease progresses to end-stage renal disease. There are currently no effective drugs available to treat kidney fibrosis, so traditional medicine is likely to be a candidate. The therapeutic potential of saikosaponin B2 (SSB2), a biologically active ingredient of Radix Bupleuri, on renal fibrosis has not been reported. Methods A unilateral ureteral obstruction (UUO) model was conducted to induce renal interstitial fibrosis in mice. SSB2’s effect was valuated by histological staining and exploring the changes in expression of relative proteins and mRNAs. A conditional medium containing sonic hedgehog variant protein stimulating normal rat kidney interstitial fibroblast cells (NRK-49F) was used in an in vitro model to determine the possible mechanism. The molecular target of SSB2 was verified using several mutation plasmids. Results SSB2 administration reduced kidney injury and alleviated interstitial fibrosis by decreasing excessive accumulation of extracellular matrix components in UUO mice. It could also reduce the expression of α-SMA, fibronectin and Gli1, a crucial molecule of the hedgehog (Hh) signaling pathway both in vivo and in vitro. In NIH-3T3 cells simulated by conditional medium containing sonic hedgehog variant protein, SSB2 showed the ability to decrease the expression of Gli1 and Ptch1 mRNA. Using a dual-luciferase reporter assay, SSB2 suppressed the Gli-luciferase reporter activity in NIH-3T3 cells, and the IC50 was 0.49 μM, but had no effect on the TNF-α/NF-κB and Wnt/β-catenin signaling pathways, indicating the inhibition selectivity on the Hh signaling pathway. Furthermore, SSB2 failed to inhibit the Hh pathway activity evoked by ectopic expression of Gli2ΔN and Smo D473H, suggesting that SSB2 might potentially act on smoothened receptors. Conclusion SSB2 could attenuate renal fibrosis and decrease fibroblast activation by inhibiting the Hh signaling pathway. |
| Databáze: | OpenAIRE |
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