The Multi-Layered Effect of Panaxatriol Saponins in Preventing Diabetic Nephropathy in Mice

Background: Diabetic nephropathy (DN) is a common microvascular complication of diabetes and the leading cause of end-stage renal disease (ESRD). Nearly 40% of people with diabetes will develop DN, and DN accounts for 23% of ESRD cases in China. Dysfunction of the gut-kidney axis, characterized by impaired intestinal barrier function and gut microbiota dysbiosis, exacerbates renal inflammation and fibrosis under sustained hyperglycemia. Panaxatriol saponins (PTS), bioactive constituents of the traditional Chinese medicine Panax notoginseng , have been reported to improve blood circulation, resolve stasis, enhance microcirculation, and improve vascular function. However, the effects of PTS on DN are unknown. This study sought to investigate the effect and underlying mechanism of PTS in DN. Methods: Male C57BLKs/J db./m and db./db. mice (8-9 weeks old; 23-25 g) were selected. For db./db. mice, three doses (30, 60, and 120 mg/kg) of PTS, as well as positive controls Irbesartan and Keluoxin, were administered orally to evaluate their effects. Several tests were conducted, including serum analysis, kidney histology, electron microscopy, Western blotting, immunofluorescence, qRT-PCR, 16S rRNA gene sequencing, RNA-sequencing, and metabolomic analysis. Results: PTS significantly reduced albuminuria, improved dyslipidemia, and decreased systemic inflammation in DN mice. It also outperformed two positive-control drugs in mitigating glomerular glycogen deposition, collagen accumulation, basement membrane thickening, and podocyte injury; it downregulated renal pro-inflammatory cytokines and fibrotic markers, probably by suppressing TNF, PI3K-Akt, JAK-STAT, and ECM signaling pathways. PTS restored intestinal tight-junction genes (Tjp1, Occludin, Jam-1) and E-cadherin to repair intestinal barrier damage. It reversed gut microbiota dysbiosis by upregulating protective Ligilactobacillus and decreasing harmful HT002 . Twelve co-altered gut-kidney metabolites were identified, which were closely correlated with renal inflammatory and fibrotic gene programs; PTS reversed these metabolic disturbances at the same time. Conclusion: These findings indicate that PTS mitigate the progression of DN due to its integrated effects on renal inflammation/fibrosis, intestinal barrier integrity, and gut microbiota composition. The ability of PTS to modulate the gut-kidney axis suggests a promising therapeutic strategy for DN, thereby addressing the pressing clinical demand for effective interventions.