Targeting renal OATs to develop renal protective agent from traditional Chinese medicines: Protective effect of Apigenin against Imipenem-induced nephrotoxicity
Targeting renal OATs to develop renal protective agent from traditional Chinese medicines: Protective effect of Apigenin against Imipenem-induced nephrotoxicity
复制标题
靶向肾OATs开发中药肾保护剂：芹菜素对亚胺培南肾毒性的保护作用
DOI：
10.1002/ptr.6727
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发表时间：
2020-05-28
影响因子：
7.2
通讯作者：
Liu, Kexin
中科院分区：
文献类型：
--
作者：
Huo, Xiaokui;Meng, Qiang;Liu, Kexin
亚胺培南（Imp）是一种广泛使用的广谱抗生素。但肾脏不良反应限制了其临床应用。我们以前报道过有机阴离子转运体（OATs）促进Imp的肾转运并导致其肾毒性。天然黄酮类化合物具有肾脏保护作用。在此，我们旨在从中药中开发有效的OAT抑制剂，并评估其对imp引起的肾毒性的保护作用。在50种中药中，三蒺藜、鸭梨和番茄对OAT1/3有较强的抑制作用。经筛选其主要成分后，芹菜素对OAT1/3- hek293细胞的Imp摄取有较强的抑制作用，IC50值分别为1.98 +/- 0.36 μ M （OAT1）和2.29 +/- 0.88 μ M （OAT3）。此外，Imp表现出oat1 /3依赖性的细胞毒性，芹菜素减轻了这种毒性。此外，芹菜素改善了Imp诱导的兔肾毒性，减少了Imp在肾脏中的分泌。芹菜素抑制了Imp在细胞内的积累，从而降低了兔原发性近端小管细胞（rPTCs）的肾细胞毒性。芹菜素是一种广泛存在于中草药中的黄酮，是一种有效的OAT1/3抑制剂。芹菜素通过抑制OAT，至少在一定程度上减少了Imp的肾脏暴露，从而防止Imp的肾毒性。芹菜素可以作为临床上减少Imp肾脏不良反应的有希望的药物。
Imipenem (Imp) is a widely used broad-spectrum antibiotic. However, renal adverse effects limit its clinical application. We previously reported that organic anion transporters (OATs) facilitated the renal transport of Imp and contributed its nephrotoxicity. Natural flavonoids exhibited renal protective effect. Here, we aimed to develop potent OAT inhibitors from traditional Chinese medicines (TCMs) and to evaluate its protective effect against Imp-induced nephrotoxicity. Among 50 TCMs, Tribuli Fructus, Platycladi Cacumen, and Lycopi Herba exhibited potent inhibition on OAT1/3. After screening their main components, Apigenin strongly inhibited Imp uptake by OAT1/3-HEK293 cells with IC50 values of 1.98 +/- 0.36 mu M (OAT1) and 2.29 +/- 0.88 mu M (OAT3). Moreover, Imp exhibited OAT1/3-dependent cytotoxicity, which was alleviated by Apigenin. Furthermore, Apigenin ameliorated Imp-induced nephrotoxicity in rabbits, and reduced the renal secretion of Imp. Apigenin inhibited intracellular accumulation of Imp and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells (rPTCs). Apigenin, a flavone widely distributed in TCMs, was a potent OAT1/3 inhibitor. Through OAT inhibition, at least in part, Apigenin decreased the renal exposure of Imp and consequently protected against the nephrotoxicity of Imp. Apigenin can be used as a promising agent to reduce the renal adverse reaction of Imp in clinic.