Kaempferide通过抑制氧化应激和诱导自噬来改善顺铂诱导的肾毒性
Kaempferide ameliorates cisplatin-induced nephrotoxicity via inhibiting oxidative stress and inducing autophagy
影响因子:8.40000
分区:医学2区 / 药学1区 化学：综合2区
发表日期:2023 Jul
作者:
Yan-Fei Shao, Bing-Bing Tang, Yu-Hui Ding, Chun-Yan Fang, Ling Hong, Chun-Xiao Shao, Zhao-Xu Yang, Yue-Ping Qiu, Jin-Cheng Wang, Bo Yang, Qin-Jie Weng, Jia-Jia Wang, Qiao-Jun He
摘要
由抗肿瘤药物（例如顺铂）引起的急性肾损伤（AKI）是一种严重的并发症，目前尚无有效治疗，导致化学疗法的降低或终止。天然产物或草药逐渐被认为是针对顺铂诱导的AKI的有前途的药物，具有多靶向，多效和耐药性的优势。在这项研究中，我们研究了Kaempferide的作用，Kaempferide是一种从Kaempferia Galanga根茎中提取的天然类黄酮，体外和体内实验性AKI模型。我们首先在小鼠中进行了药代动力学研究，并发现了kaempferide的相对稳定状态，少量转化为kaempferol。我们表明，Kaempferide（10μM）和Kaempferol（10μM）在永生的近端小管上皮细胞系HK-2中都显着抑制了顺铂引起的损伤。在通过注射单剂量的顺铂（15 mg/kg）诱导的AKI小鼠中，口服kaempferide（50 mg/kg）在顺铂注射明显改善肾功能之前或之后，并改善了肾脏组织损伤。我们证明，Kaempferide抑制了顺铂治疗的小鼠和HK-2细胞中氧化应激和诱导的自噬，从而增加了肾小管细胞活力并减少免疫反应以减轻疾病进展。此外，用kaempferide的治疗显着改善了体外和体内的缺血诱导的肾脏损伤。我们得出的结论是，Kaempferide是治疗各种AKI的有前途的天然产品。这项研究对促进其在医疗产品中的使用有很大的影响，并有助于突破诊所中顺铂的有限使用。
Abstract
Acute kidney injury (AKI) caused by anti-tumor drugs, such as cisplatin, is a severe complication with no effective treatment currently, leading to the reduction or discontinuation of chemotherapy. Natural products or herbal medicines are gradually considered as promising agents against cisplatin-induced AKI with the advantages of multi-targeting, multi-effects, and less resistance. In this study, we investigated the effects of kaempferide, a natural flavonoid extracted from the rhizome of Kaempferia galanga, in experimental AKI models in vitro and in vivo. We first conducted pharmacokinetic study in mice and found a relative stable state of kaempferide with a small amount of conversion into kaempferol. We showed that both kaempferide (10 μM) and kaempferol (10 μM) significantly inhibited cisplatin-caused injuries in immortalized proximal tubule epithelial cell line HK-2. In AKI mice induced by injection of a single dose of cisplatin (15 mg/kg), oral administration of kaempferide (50 mg/kg) either before or after cisplatin injection markedly improved renal function, and ameliorated renal tissue damage. We demonstrated that kaempferide inhibited oxidative stress and induced autophagy in cisplatin-treated mice and HK-2 cells, thus increasing tubular cell viability and decreasing immune responses to attenuate the disease progression. In addition, treatment with kaempferide significantly ameliorated ischemia-reperfusion-induced renal injury in vitro and in vivo. We conclude that kaempferide is a promising natural product for treating various AKI. This study has great implications for promotion of its use in healthcare products, and help to break through the limited use of cisplatin in the clinic.