Abstract
BackgroundP-glycoprotein (P-gp)-mediated steroid resistance (SR) has been suggested to play a significant role in lupus nephritis (LN) treatment failure. Panax notoginseng saponins (PNS), the main effective components of the traditional Chinese medicine notoginseng, exhibited potent reversal capability of P-gp-mediated SR, but its mechanism remains unknown. This study aimed to investigate the effect of PNS on reversing SR in lupus and its underlying mechanism in vivo and in vitro.MethodsIn this study, an SR animal and splenic lymphocyte model were established using low-dose methylprednisolone (MP). Flow cytometry was used to detect the effect of PNS on reversing P-gp-mediated SR and the expression of P-gp in different T-cells phenotypes. Serum levels of ANA and dsDNA in lupus mice were measured by ELISA. Apoptosis was identified by Annexin V-FITC/PI staining. RT–PCR and Western blotting were used to detect the protein and mRNA expression levels of SIRT1, FoxO1, and MDR1 in SR splenic lymphocytes from lupus mice (SLCs/MPs).ResultsPNS could reverse the SR in lupus mice. Simultaneously, PNS increased the apoptotic effect of MP on SLCs/MP cells. The increased accumulation of rhodamine-123 (Rh-123) indicated that intracellular steroid accumulation could be increased by the action of PNS. Moreover, PNS decreased the expression of P-gp levels. Further experiments elucidated that the SIRT1/FoxO1/MDR1 signalling pathway existed in SLCs/MP cells, and PNS suppressed its expression level to reverse SR. The expression of P-gp in Th17 from SLCs/MP cells was increased, while PNS could reduce its level in a more obvious trend.ConclusionThe present study suggested that PNS reversed P-gp-mediated SR via the SIRT1/FoxO1/MDR1 signalling pathway, which might become a valuable drug for the treatment of SR in lupus. Th17 might be the main effector cell of PNS reversing SR.
Highlights
P-glycoprotein (P-gp)-mediated steroid resistance (SR) has been suggested to play a significant role in lupus nephritis (LN) treatment failure
To determine whether Panax notoginseng saponins (PNS) can reverse SR in lupus mice, the expression of P-gp and the accumulation of Rh-123 in splenic lymphocytes from SR lupus mouse (SRLM)-treated mice were measured by flow cytometry, and the levels of ANA and dsDNA in serum were examined by enzyme-linked immunosorbent assay (ELISA)
The flow cytometry results showed that, compared with the SR control group and SR with high-dose methylpred‐ nisolone (MP) group, the expression of P-gp was downregulated and the accumulation of rhodamine-123 in splenic lymphocytes was increased in the high-dose PNS and TQR groups; PNS had a significant ability to reverse SR in lupus mice (Fig. 1A,B)
Summary
P-glycoprotein (P-gp)-mediated steroid resistance (SR) has been suggested to play a significant role in lupus nephritis (LN) treatment failure. Pan et al BMC Complementary Medicine and Therapies (2022) 22:13 overactivated B lymphocytes, producing a large number of autoantibodies and immune complexes, which has complicated clinical presentations and involves multiple systems and organs [1, 2]. A basic drug for the treatment of lupus, can directly act on lymphocytes, inhibit antibody formation, effectively prevent inflammatory reactions, quickly relieve clinical symptoms, and prevent the further progression of disease [3, 4]. Studies have shown that one of the key mechanisms of immunosuppressants such as cyclosporine A and tacrolimus on immune response and SR is the selective inhibition of Th17 cells [11, 12]
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