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Ginsenoside CK potentiates SIRT1 to alleviate lupus nephritis through compensating for XBP1-mediated endoplasmic
Ziyu Song1, Ying Li2, Sumei Xu1
1General Practice, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310000, China.
Abstract:
Immune complex deposition is a critical factor in early renal damage associated with lupus nephritis (LN), and targeting plasma cell aggregation offers a promising therapeutic strategy. Ginsenoside compound K (i.e., 20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol) (CK), a derivative of ginsenoside, has indicated significant potential in alleviating renal damage in lupus-prone mice, potentially by modulating B cell dynamics in response to endoplasmic reticulum (ER) stress. In this study, CK (20 or 40 mg/kg) was orally administered to female MRL/lpr mice for 10 weeks. The effects of CK on B cell subpopulations, renal function, and histopathological changes were evaluated. Single-cell ribonucleic acid sequencing was employed to analyze gene expression profile and pseudotime trajectories during B cell-mediated renal injury. Additionally, in vitro B cell assays were conducted to explore the role of the sirtuin-1 (SIRT1)-X-box binding protein 1 (XBP1) axis in ER stress. Our findings demonstrated that CK effectively reduced anti-double stranded DNA (dsDNA) antibody levels, alleviated systemic inflammation, improved renal function, and facilitated the clearance of deposited immune complexes. CK likely suppressed the unfolded protein response (UPR), delaying the differentiation of renal-activated B cells into plasma cells. It promoted B cell-specific SIRT1 activation and inhibited the splicing of XBP1 into its active form, XBP1s. CK also restored ER morphology by interacting with calmodulin (CALM) to maintain ER calcium storage, reinforcing SIRT1 functional integrity and promoting XBP1 deacetylation, thereby limiting plasma cell differentiation. In conclusion, CK mitigates plasma cell accumulation in the renal microenvironment by preventing SIRT1-mediated XBP1 splicing, offering a potential therapeutic approach for LN.
Insights
Ginsenoside compound K (CK) reduces kidney damage in lupus nephritis by inhibiting plasma cell formation. CK targets the SIRT1-XBP1 pathway, alleviating inflammation and improving renal function in mice.
Area of Science:
- Immunology
- Nephrology
- Pharmacology
Background:
- Immune complex deposition drives lupus nephritis (LN) renal damage.
- Targeting plasma cell aggregation is a potential therapeutic strategy for LN.
- Ginsenoside compound K (CK) shows promise in alleviating renal damage in lupus-prone models.
Purpose of the Study:
- To investigate the therapeutic effects of CK on B cell dynamics and renal injury in MRL/lpr mice.
- To explore the underlying mechanisms of CK action, focusing on the endoplasmic reticulum (ER) stress pathway.
Main Methods:
- Oral administration of CK (20 or 40 mg/kg) to MRL/lpr mice for 10 weeks.
- Evaluation of B cell subpopulations, renal function, and histopathology.
- Single-cell RNA sequencing and in vitro B cell assays to analyze gene expression and the SIRT1-XBP1 axis.
Main Results:
- CK reduced anti-dsDNA antibodies, systemic inflammation, and immune complex deposition, improving renal function.
- CK suppressed the unfolded protein response (UPR), delaying B cell differentiation into plasma cells.
- CK activated SIRT1, inhibited XBP1 splicing, restored ER morphology, and limited plasma cell differentiation.
Conclusions:
- CK mitigates plasma cell accumulation in the renal microenvironment of LN models.
- CK acts by preventing SIRT1-mediated XBP1 splicing, offering a potential therapeutic strategy for LN.
