Total Panax notoginseng saponins treats diabetic kidney disease in mice by regulating the TXNIP/NLRP3 signaling pathway

The escalating diabetes pandemic presents a critical worldwide healthcare burden, with diabetic kidney disease (DKD) emerging as a predominant microvascular complication that frequently progresses to renal functional impairment. Current clinical interventions lack effective therapeutics to halt DKD progression. This study examines the nephroprotective mechanisms of Total Panax Notoginseng Saponins (TPNS) against DKD using cellular and animal models. In vitro, MPC-5 podocytes were exposed to elevated glucose concentrations (30 mM HG), with TPNS co-treatment (20 μg/mL). In vivo, Type 2 DKD was modeled using C57BLKs db/db mice treated orally with TPNS (50/100 mg/kg/day) for 8 weeks. Assessments included biochemical assays, confocal microscopy, flow cytometry, and Western blotting. In vitro,TPNS effectively counteracted HG-induced oxidative stress by inhibiting the PI3K/AKT signaling cascade, promoting NRF2 translocation into the nucleus and upregulating downstream antioxidant enzymes (HO-1, NQO1). This intervention simultaneously reduced both cytoplasmic and mitochondrial ROS levels (P<0.001) while downregulating TXNIP/NLRP3 pathway components (P<0.01). Animal experiments demonstrated that, TPNS significantly Reduced blood glucose, urinary protein, BUN, and creatinine (P<0.01), decreased the renal IL-6 and oxidative markers (8-OHdG, MDA). And ameliorated glomerular hypertrophy and tubular injury. TPNS mitigates DKD progression through dual modulation of PI3K/AKT/NRF2 axis and TXNIP/NLRP3 pathway. These findings position TPNS as a multitarget therapeutic candidate for DKD.