Journal of ethnopharmacology · 2025
Reducing the NFAT-uPAR signal of podocyte injury exerts the effect of Danggui-Shaoyao-San in improving proteinuria in nephrotic syndrome.
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Zhang Xiaohan, Ding Ye, Zhang Chunjie, Han Wenjin, Yu Xuelong, Wang Yunlai, Xu Fan
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Danggui-Shaoyao-San (DSS), originated from Synopsis of Golden Chamber, a classic medical work of the Han Dynasty, is an archetypal formula for promoting blood circulation and diuresis. It has shown efficacy in improving renal function, and relieving proteinuria, thus achieving the effect of treating nephrotic syndrome (NS).
THE PURPOSE OF THE STUDY: To investigate the mechanism of DSS in reducing podocyte injury and improving proteinuria in NS.
METHODS: The potential targets and mechanisms of DSS in the treatment of NS were screened by network pharmacology and molecular docking, and the quality of DSS extract was controlled by HPLC and UPLC-Q/TOF-MS. Subsequently, an NS model was induced in rats via tail vein injection of adriamycin (ADR). The rats were randomly divided into DSS low-, medium-, and high-dose groups, as well as a positive control group treated with cyclosporin A (CsA), administered by daily gavage for 4 weeks. Dynamic assessments were performed to measure 24 h urinary protein levels and serum biochemical parameters. Kidney tissues were analyzed using transmission electron microscopy to observe foot process morphology. In vitro studies utilized 1 μM ADR to induce injury in human glomerular podocytes (HGPCs), followed by intervention with DSS-containing serum. The expressions of synaptopodin, nephrin, nuclear translocation of nuclear factor of activated T cells c1 (NFATc1) and urokinase-type plasminogen activator receptor (uPAR)/integrin αvβ3 axis in vivo and in vitro were detected by ELISA, Western blot and immunofluorescence, respectively.
RESULTS: Network pharmacology revealed that DSS contains 34 active components capable of targeting key NS-related proteins, including NFATc1, uPAR, and Integrin αvβ3, as confirmed by molecular docking studies. In the NS rat model, DSS dose-dependently reduced 24 h urine protein excretion, improved serum biochemical parameters, mitigated pathological damage, and significantly repaired podocyte structure integrity. Both in vivo and in vitro experiments demonstrated that DSS extract and DSS-containing serum could restore the expression levels of synaptopodin and nephrin protein, inhibit NFATc1 nuclear translocation, and decrease the expression of uPAR and integrin αvβ3 after podocyte injury. The alteration of the above signals by DSS is similar to that of the NFAT inhibitor 11R-VIVIT.
CONCLUSIONS: DSS may alleviate podocyte injury by regulating NFAT-uPAR signaling pathway, and then improve NS proteinuria.
THE PURPOSE OF THE STUDY: To investigate the mechanism of DSS in reducing podocyte injury and improving proteinuria in NS.
METHODS: The potential targets and mechanisms of DSS in the treatment of NS were screened by network pharmacology and molecular docking, and the quality of DSS extract was controlled by HPLC and UPLC-Q/TOF-MS. Subsequently, an NS model was induced in rats via tail vein injection of adriamycin (ADR). The rats were randomly divided into DSS low-, medium-, and high-dose groups, as well as a positive control group treated with cyclosporin A (CsA), administered by daily gavage for 4 weeks. Dynamic assessments were performed to measure 24 h urinary protein levels and serum biochemical parameters. Kidney tissues were analyzed using transmission electron microscopy to observe foot process morphology. In vitro studies utilized 1 μM ADR to induce injury in human glomerular podocytes (HGPCs), followed by intervention with DSS-containing serum. The expressions of synaptopodin, nephrin, nuclear translocation of nuclear factor of activated T cells c1 (NFATc1) and urokinase-type plasminogen activator receptor (uPAR)/integrin αvβ3 axis in vivo and in vitro were detected by ELISA, Western blot and immunofluorescence, respectively.
RESULTS: Network pharmacology revealed that DSS contains 34 active components capable of targeting key NS-related proteins, including NFATc1, uPAR, and Integrin αvβ3, as confirmed by molecular docking studies. In the NS rat model, DSS dose-dependently reduced 24 h urine protein excretion, improved serum biochemical parameters, mitigated pathological damage, and significantly repaired podocyte structure integrity. Both in vivo and in vitro experiments demonstrated that DSS extract and DSS-containing serum could restore the expression levels of synaptopodin and nephrin protein, inhibit NFATc1 nuclear translocation, and decrease the expression of uPAR and integrin αvβ3 after podocyte injury. The alteration of the above signals by DSS is similar to that of the NFAT inhibitor 11R-VIVIT.
CONCLUSIONS: DSS may alleviate podocyte injury by regulating NFAT-uPAR signaling pathway, and then improve NS proteinuria.