Department of Pharmacology, College of Basic Medicine, Changchun University of Chinese Medicine, Changchun 130117, China.
Department of Pathology, The First Hospital of Jilin University, Changchun 130000, China.
Int Immunopharmacol. 2018 Oct;63:227-238. doi: 10.1016/j.intimp.2018.07.027. Epub 2018 Aug 11.
Though the antidiabetic effect of ginsenoside compound K (CK) has been well studied, the effect of CK on diabetic nephropathy (DN) is not clear. Whether CK would have a protective effect against DN and it could exert the protective effect by inhibiting the oxidative stress, NLRP3 inflammasome and NF-κB/p38 signaling pathway were investigated in this study. Here, the HFD (high fat diet)/STZ (streptozotocin)-induced DN mice model was established to assess the CK effect in vivo. Parallel experiments uncovering the molecular mechanism by which CK prevents from DN was performed in rat glomerular mesangial cell line HBZY-1 exposed to high glucose. CK (10, 20, 40 mg/kg/day) were intragastrically administered for 8 weeks, the general status, biochemical parameters, renal pathological changes and oxidative stress-parameters were observed, and the NLRP3 inflammasome and NF-κB/p38 signaling pathway were evaluated. The results showed that the elevated fasting blood glucose, serum creatinine, blood urea nitrogen and 24-hour urine protein of the DN mice were significantly decreased, and the proliferation of glomerular mesangial matrix was alleviated by CK. In addition, the generation of ROS in the kidney was significantly decreased, and the expression of Nox1 and Nox4 proteins were down-regulated. Further, the expression of NLRP3 inflammasome components (NLRP3, ASC and Caspase-1) and the inflammatory cytokines IL-1β and IL-18 were also significantly down-regulated in vivo and in vitro. The phosphorylation of renal p38 MAPK was also inhibited by CK. MCC950 (an inhibitor of NLRP3 inflammasome) and VX-765 (a Caspase-1 Inhibitor) showed significant interaction with CK on the decrease of IL-1β concentration in HBZY-1 cells. In conclusion, our study provided evidence that the protective effect of CK on diabetes-induced renal injury is associated with down-regulating the expression of NADHP oxidase, and inhibition of ROS-mediated activation of NLRP3 inflammasome and NF-κB/p38 signaling pathway, suggesting its therapeutic implication for renal inflammation.
虽然已对人参皂苷Compound K（CK）的降血糖作用进行了深入研究，但 CK 对糖尿病肾病（DN）的作用尚不清楚。本研究旨在探讨 CK 是否对 DN 具有保护作用，以及其是否通过抑制氧化应激、NLRP3 炎性体和 NF-κB/p38 信号通路发挥保护作用。为此，建立了高脂肪饮食（HFD）/链脲佐菌素（STZ）诱导的 DN 小鼠模型，以评估 CK 在体内的作用。同时，在高糖诱导的大鼠肾小球系膜细胞系 HBZY-1 中进行了平行实验，以揭示 CK 预防 DN 的分子机制。CK（10、20、40mg/kg/天）连续灌胃 8 周，观察一般状态、生化参数、肾脏病理变化和氧化应激参数，并评估 NLRP3 炎性体和 NF-κB/p38 信号通路。结果表明，DN 小鼠的空腹血糖、血清肌酐、血尿素氮和 24 小时尿蛋白明显降低，肾小球系膜基质增生减轻。此外，CK 可显著降低肾脏 ROS 的生成，下调 Nox1 和 Nox4 蛋白的表达。进一步研究发现，CK 还可下调 NLRP3 炎性体各组成部分（NLRP3、ASC 和 Caspase-1）和炎性细胞因子 IL-1β和 IL-18 的表达，同时抑制肾脏 p38MAPK 的磷酸化。NLRP3 炎性体抑制剂 MCC950 和 Caspase-1 抑制剂 VX-765 与 CK 联合使用可显著降低 HBZY-1 细胞中 IL-1β 的浓度。综上所述，本研究表明 CK 对糖尿病诱导的肾损伤的保护作用与下调 NADPH 氧化酶的表达有关，可抑制 ROS 介导的 NLRP3 炎性体和 NF-κB/p38 信号通路的激活，提示其对肾脏炎症具有治疗作用。
