Puerarin reduces diabetic nephropathy-induced podocyte pyroptosis by modulating the SIRT1/NLRP3/caspase-1 pathway

Background: Chronic kidney inflammation and podocyte injury are key pathological features of Diabetic Nephropathy (DN). Puerarin has been shown to inhibit podocyte pyroptosis and provide renal protection, although its molecular mechanism remains unclear.

Methods: The effects and mechanisms of puerarin on podocyte pyroptosis were investigated in a DN mouse model. In vivo, a DN model was established using streptozotocin (STZ) and treated with puerarin, a SIRT1 agonist, or a SIRT1 inhibitor. In vitro, a podocyte pyroptosis model was induced under high glucose (HG) conditions, and lentivirus transfection was used to either silence or overexpress SIRT1. Techniques including ELISA, transmission electron microscopy, flow cytometry, PCR, and Western blotting were employed to explore the molecular mechanisms by which puerarin inhibits podocyte pyroptosis.

Results: The study showed that SIRT1 expression was significantly downregulated in STZ-induced DN mice and HG-induced MPC-5 cell pyroptosis models. Overexpression of SIRT1 decreased the secretion of inflammatory factors, reduced reactive oxygen species (ROS) release, improved podocyte injury, restored podocyte function, and inhibited the expression of the NLRP3 inflammasome and its downstream factors. Furthermore, puerarin increased SIRT1 expression in DN mice and HG-treated MPC-5 cells, inhibited the activation of the NLRP3/Caspase-1 pathway, reduced podocyte pyroptosis, and alleviated renal inflammatory damage.

Conclusion: These findings suggest that puerarin may inhibit podocyte pyroptosis, reduce podocyte injury, and mitigate renal inflammatory damage by modulating the SIRT1/NLRP3/Caspase-1 pathway.