Panax notoginseng saponins attenuate glomerular endothelial glycocalyx degradation in diabetic nephropathy
- Phytomedicine. 2026 Jun 23:159:158486. doi: 10.1016/j.phymed.2026.158486.
- 1. College of Fisheries and Life Science, Shanghai Ocean University, No. 999, Hucheng Ring Road, Pudong New Area, Shanghai, 201306, China.
- 2. Shanghai Jiao Tong University School of Medicine No. 227, Chongqing South Road, Huangpu District, Shanghai, 200025, China.
- 3. Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 222, Huanhu West 3rd Road, Nanhui New City, Pudong New Area, Shanghai, China. Electronic address: [email protected].
Background: Glomerular endothelial glycocalyx (eGC) degradation and shedding play key roles in diabetic nephropathy (DN) pathogenesis. Although Panax notoginseng saponins (PNS) have been utilized clinically for diabetes and its complications, the mechanisms by which PNS protects against glomerular eGC degradation, particularly through heparanase-1 (HPSE1)-mediated pathways, remain unclear.
Purpose: This study investigated whether PNS protects against glomerular eGC injury in DN by regulating the HPSE1/EGFR/STAT3 signaling axis.
Methods: In vitro cell models and in vivo animal models of DN were established using mouse renal glomerular endothelial cells (MRGECs) stimulated with high glucose/high palmitic acid (HGHF) and db/db mice, respectively. The effects of PNS on glomerular eGC integrity and endothelial injury were evaluated. The underlying mechanisms were examined using Western blotting, immunofluorescence staining, transmission electron microscopy, quantitative Real-Time PCR, siRNA-mediated HPSE1 knockdown, and lentivirus- or adeno-associated virus-mediated HPSE1 overexpression.
Results: HGHF stimulation upregulated HPSE1 expression and induced eGC degradation in MRGECs, whereas PNS treatment suppressed HPSE1 expression and preserved eGC integrity. In db/db mice, PNS administration improved renal injury, reduced HPSE1 expression, and attenuated glomerular eGC degradation. Mechanistically, HPSE1 overexpression promoted heparan sulfate (HS) degradation, reduced syndecan-1 (SDC-1) expression, and enhanced EGFR and STAT3 phosphorylation, thereby aggravating eGC injury. In contrast, HPSE1 knockdown or PNS treatment mitigated these changes. Furthermore, AAV-mediated HPSE1 overexpression exacerbated glomerular eGC injury in db/db mice, whereas PNS treatment partially reversed this effect.
Conclusion: PNS protects against DN-associated glomerular endothelial injury by attenuating eGC degradation, at least in part through suppression of the HPSE1/EGFR/STAT3 signaling axis. This study provides fresh mechanistic insights into how PNS exerts renoprotective effects, suggesting that HPSE1-mediated eGC degradation is a promising target for preventing and treating DN.