Kaempferide ameliorates cisplatin-induced nephrotoxicity via inhibiting oxidative stress and inducing autophagy
Kaempferide ameliorates cisplatin-induced nephrotoxicity via inhibiting oxidative stress and inducing autophagy
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DOI：
10.1038/s41401-023-01051-4
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发表时间：
2023-01
影响因子：
8.2
通讯作者：
Y. Shao;Bing-Bing Tang-Bing;Yuwen Ding;Chun-yan Fang;Ling Hong;Chun-Xiao Shao;Zhao-xu Yang;Yueping Qiu;Jin-cheng Wang;Bo Yang;Qin-jie Weng;Jia-jia Wang;Qiao‐jun He
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文献类型：
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作者：
Y. Shao;Bing-Bing Tang-Bing;Yuwen Ding;Chun-yan Fang;Ling Hong;Chun-Xiao Shao;Zhao-xu Yang;Yueping Qiu;Jin-cheng Wang;Bo Yang;Qin-jie Weng;Jia-jia Wang;Qiao‐jun He
顺铂等抗肿瘤药物所致的急性肾损伤(AKI)是目前尚无有效治疗方法的严重并发症，导致化疗的减少或停止。天然药物或中草药因具有多靶点、多效应、耐药性小等优点，逐渐被认为是治疗顺铂所致急性KI的有效药物。在本研究中，我们研究了山奈德，一种从山茶根茎中提取的天然黄酮类化合物，在体内外对实验性AKI模型的影响。我们首先在小鼠体内进行了药代动力学研究，发现山奈德处于相对稳定的状态，并有少量转化为山奈酚。我们发现，山奈德(10 μM)和山奈酚(10 μM)均能显著抑制顺铂诱导的永生化近端小管上皮细胞系HK-2的损伤。在单次注射顺铂(15 mg/kg)诱导的急性肾损伤小鼠中，顺铂注射前或注射后口服山奈德(50 mg/kg)均能明显改善肾功能，减轻肾组织损伤。我们证明，山奈德能抑制顺铂处理的小鼠和HK-2细胞的氧化应激和诱导自噬，从而提高肾小管细胞的活力，降低免疫反应，从而延缓疾病的进展。此外，在体外和体内，山奈德治疗显著改善了缺血再灌注所致的肾脏损伤。我们认为，山奈德是一种很有前途的治疗各种AKI的天然产物。本研究对其在保健品中的推广应用具有重要意义，有助于突破顺铂在临床应用的局限性。
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 ofKaempferia 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.