Spatially resolved multi-omics reveals that paeoniflorin ameliorates IgA nephropathy via Oat, Aco1 and Fh-mediated metabolic reprogramming and tubuloimmune crosstalk.

BACKGROUND

Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis globally, leads to a high lifetime risk of kidney failure. Shenhua Tablet (SHT), a Chinese herbal formula, demonstrates clinical efficacy in IgAN. Paeoniflorin (PF), its principal active constituent, shows anti-inflammatory and renoprotective effects in preclinical models; however, its precise molecular mechanisms in IgAN remain unclear.

PURPOSE: This study aimed to elucidate the spatial molecular mechanisms underlying the therapeutic effect of PF in IgAN using an integrated multi-omics approach.

STUDY

DESIGN

A rat model of IgAN was established by intravenous injection of Thy-1 antibody in Wistar rats. This model was used to evaluate the renoprotective efficacy of PF, and the core pathways mediating its therapeutic effects were further investigated.

METHODS

We applied an integrated spatial multi-omics approach, combining spatial metabolomics (SM) and spatial transcriptomics (ST), to investigate region-specific metabolic and transcriptional reprogramming in the kidney following PF treatment in IgAN model rats. Key findings were further validated through in vitro functional experiments.

RESULTS

Our results uncovered spatially heterogeneous therapeutic effects of PF, corresponding to regional pathological variations in IgAN-induced renal injury. Spatial multi-omics analysis further revealed substantial regional heterogeneity in both metabolic activity and transcriptional profiles. In the renal cortex (CTX), PF administration induced region-specific metabolic reprogramming, primarily through Oat, Aco1, Fh mediated disruption of the TCA cycle, accompanied by upregulation of arginine and proline metabolism. Additionally, we observed a decreased proportion and diminished co-localization of injured distal tubule cells (DTCs) in the CTX. These multi-omics insights were further validated through in vitro functional assays, confirming PF's regulation of the Oat, Aco1, Fh and its role in attenuating inflammatory responses.

CONCLUSION

These findings provide novel spatial perspectives on the molecular pathogenesis of IgAN and clarify the therapeutic mechanisms of PF, offering potential targets for developing more effective strategies to alleviate the global burden of this renal disease.