Oxymatrine Attenuates High Glucose-induced NLRP3 Inflammasome-dependent Pyroptosis and Injury in Podocytes by Regulating SIRT1/NF-κB Pathway.

Diabetic nephropathy is a microvascular complication that leads to renal injury. Oxymatrine (OMT) is a matrine alkaloid and has been shown to ameliorate diabetic nephropathy. However, it is still unknown whether its mechanism involves podocytes, which play a critical role in diabetic nephropathy. High glucose-induced podocytes (MPC5) were treated with OMT, the NOD-like receptor protein 3 (NLRP3) inhibitor MCC950, and the sirtuin 1 (SIRT1) inhibitor EX527. The effects on podocyte proliferation and apoptosis were assessed using cell counting kit-8 and flow cytometry. Immunofluorescence staining was performed to detect the expression of podocyte-associated proteins, NLRP3 inflammasome, and SIRT1. The levels of interleukin (IL)-1β and IL-18 were measured by enzyme-linked immunosorbent assay. Additionally, Western blot analysis was conducted to evaluate podocyte-related proteins, NLRP3 inflammasome-dependent pyroptosis-related proteins, and SIRT1/nuclear factor kappa B (NF-κB) pathway proteins, aiming to elucidate the mechanisms by which OMT improves podocyte injury. OMT significantly promoted the proliferation of podocytes exposed to high glucose, inhibited their apoptosis, increased the levels of nephrin, Wilms tumor 1, podocin, and zonula occludens-1, and reduced pyroptosis-related proteins, IL-1β, and IL-18 (p < 0.05). It also increased SIRT1 and decreased the acetylation of NF-κB p65 (p < 0.05). The NLRP3 inhibitor MCC950 reduced podocyte pyroptosis under high glucose conditions, while the SIRT1 inhibitor EX527 reversed the protective effects of OMT on NLRP3 inflammasome-dependent pyroptosis and podocyte injury. OMT ameliorates high glucose-induced podocyte injury by regulating the SIRT1/NF-κB pathway and inhibiting NLRP3 inflammasome-dependent pyroptosis.