山柑花素通过抑制氧化应激和诱导自噬缓解顺铂引起的肾毒性

Kaempferide ameliorates cisplatin-induced nephrotoxicity via inhibiting oxidative stress and inducing autophagy

ACTA PHARMACOLOGICA SINICA

影响因子:8.4

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

DOI: 10.1038/s41401-023-01051-4

摘要

由抗肿瘤药物如顺铂引起的急性肾损伤（AKI）是一种严重并发症，目前尚无有效治疗，导致化疗减量或中断。天然产物或草药逐渐被视为对抗顺铂引起的AKI的有潜力的药物，具有多靶点、多作用、耐药性低等优点。本研究探讨了从山柑根茎提取的天然黄酮山柑花素在体内外AKI模型中的作用。首先在小鼠中进行药代动力学研究，发现山柑花素处于相对稳定状态，少量转化为山柑甙酮。结果显示，山柑花素（10 μM）和山柑甙酮（10 μM）均显著抑制了 immortalized 近端肾小管上皮细胞系HK-2中的顺铂损伤。在单次剂量顺铂（15 mg/kg）诱导的AKI小鼠模型中，口服山柑花素（50 mg/kg）在顺铂注射前后均能显著改善肾功能，减轻肾组织损伤。研究表明，山柑花素通过抑制氧化应激和诱导自噬，提高肾小管细胞存活率，减少免疫反应，从而减缓疾病进展。此外，山柑花素治疗显著改善了体内外缺血再灌注引起的肾损伤。总之，山柑花素是一种有前景的天然产物，可用于多种AKI的治疗，对其在医疗产品中的推广具有重要意义，有助于突破临床中顺铂的有限应用。

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.