Spatially resolved multi-omics reveals the renal cortex-metabolic reprogramming of Shenhua Tablet for intervention on IgA nephropathy

Background

Shenhua tablet (SHT) is a clinically used Chinese patent medicine, which has garnered attention for its effectiveness in treating IgA nephropathy (IgAN). Nevertheless, early researches lacked anatomical and metabolic data, hindering a comprehensive understanding of the therapeutic mechanisms of SHT in spatial contexts.

Purpose

We aimed to explore the molecular mechanism of SHT intervention in IgAN by utilizing spatial multi-omics strategies.

Study design

We injected Thy-1 into tail vein to induce IgAN rat model and administer SHT. Classical pharmacological parameters were used to evaluate the efficacy of SHT. The distribution of active components of SHT and their regulation for metabolites and upstream genes in the cortex were examined to determine the intervention mechanism of SHT.

Methods

After establishing the animal models and administering SHT treatment, Kidney injury were assessed using biochemical indexes and histopathology. Classical and spatial metabolomics were employed to detect metabolites in serum and kidney. Spatial transcriptomics was used to detect mRNA levels in renal sections adjacent to the spatial metabolomics. In addition, mass-spectrometry-imaging and cell experiments were used to explore and verify the active components of SHT.

Results

SHT reduced inflammation and mesangial cell proliferation, and reversed kidney damage. Mechanically, in renal tubules, SHT regulated glutathione metabolism by reversing the expression of Gclc and Gpx3. It was further found that Pck1 and G6pc1 were increased to inhibit glycolysis. In glomeruli, SHT downregulated Oat and Odc1 and reduced spermidine and l-proline levels to inhibit mesangial cell proliferation. Finally, formononetin, calycosin and curzerenone were identified as the main active components of SHT and showed their distribution in the cortex.

Conclusions

SHT ameliorated renal injury by regulating glutathione metabolism, glycolysis, and l-proline metabolism, providing a more comprehensive insight into the molecular mechanisms of SHT intervention in IgAN in a spatial context, and offering new perspectives for the treatment of IgAN.