Ginsenoside Rg2 Alleviates HFD/STZ-Induced Diabetic Nephropathy by Inhibiting Pyroptosis via NF-κB/NLRP3 Signaling Pathways

Diabetes mellitus (DM) is considered to be the most widespread epidemic worldwide, and diabetic nephropathy (DN) is one of the most serious diabetic complications. Its complex pathogenesis makes treatment of DN an ongoing medical challenge. Ginseng (<i>Panax ginseng</i>. C. A Meyer) is a valuable medicinal herb with a long medicinal and culinary history. Ginsenoside Rg2 (Rg2), an important active component in ginseng, has effective inhibitory effects on lipogenesis and hepatic glucose production. However, the potential effect and mechanism of Rg2 on DN remain unclear. In this study, we investigated the effect of Rg2 on DN in high fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic mice and high glucose (HG)-induced human kidney 2 (HK-2) cells. The results demonstrated that Rg2 significantly improved the levels of FBG, dyslipidemia and impaired kidney function in DN mice. Additionally, Rg2 decreased the phosphorylation levels of IKKβ, IκBα, and NF-κB p65, inhibited the activation of NLRP3 inflammasomes (NLRP3, ASC, and Caspase 1), and restrained release of inflammatory factors (IL-18 and IL-1[Formula: see text]. In HG-induced HK-2 cells, Rg2 showed similar inhibitory effects on pyroptosis via NF-κB/NLRP3 signaling pathways. Moreover, the effect of Rg2 on inhibiting the activation of NF-κB/NLRP3 signaling pathways may have a relationship to reducing the overproduction of reactive oxygen species (ROS), which is further supported by the ROS inhibitor N-acetylcysteine (NAC). In conclusion, our findings clearly indicated that Rg2 could prevent the progress of DN by inhibiting the activation of pyroptosis-related NF-κB/NLRP3 signaling pathways <i>in vivo</i> and <i>in vitro</i>, suggesting that Rg2 may be a novel and promising therapeutic agent in the treatment of DN.