JBP485, A Dual Inhibitor of Organic Anion Transporters (OATs) and Renal Dehydropeptidase-I (DHP-I), Protects Against Imipenem-Induced Nephrotoxicity.
JBP485, A Dual Inhibitor of Organic Anion Transporters (OATs) and Renal Dehydropeptidase-I (DHP-I), Protects Against Imipenem-Induced Nephrotoxicity.
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JBP485 是有机阴离子转运蛋白 (OAT) 和肾脱氢肽酶-I (DHP-I) 的双重抑制剂，可防止亚胺培南引起的肾毒性
DOI：
10.3389/fphar.2022.938813
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发表时间：
2022
影响因子：
5.6
通讯作者：
Liu, Kexin
中科院分区：
文献类型：
--
作者：
Wang, Chong;Wang, Changyuan;Wu, Jingjing;Meng, Qiang;Jin, Huan;Sun, Huijun;Kaku, Taiichi;Chen, Jing;Huo, Xiaokui;Liu, Kexin
亚胺培南（IMP）具有广谱抗菌活性，但肾毒性限制了其在肾功能不全患者中的临床应用。在我们以前的研究中，发现一种二肽JBP 485（一种化学结构为环反式-4-L-羟基脯氨酰-L-丝氨酸的二肽）可减轻药物诱导的肾损伤。本研究旨在探讨JBP 485是否能减轻IMP诱导的肾损伤，并阐明其潜在的分子药代动力学机制。在兔和人肾2（HK-2）细胞中评价了JBP 485对IMP肾毒性的影响。通过大鼠药代动力学研究、肾脏代谢试验和OAT过表达细胞摄取研究，探索了有机阴离子转运蛋白（OAT）和脱氢肽酶-I（DHP-I）介导的药物相互作用（DDI）。结果显示，JBP 485显著改善IMP诱导的家兔肾毒性。此外，孵育HK-2细胞与JBP 485或西司他丁显着提高细胞存活率，抑制凋亡和减轻线粒体损伤，通过提高IMP的稳定性和减少其细胞内积累。这表明DHP-I和OAT可能参与JBP 485的保护作用。此外，与JBP 485共同施用显著增加IMP的血浆浓度以及血浆浓度-时间曲线下面积（AUC），同时降低IMP肾清除率和累积尿排泄。此外，JBP 485减少了肾切片和OAT 1/3-人胚肾293（HEK 293）细胞中的IMP摄取。JBP 485对DHP-I代谢IMP有抑制作用，IC_（50）为12.15 ± 1.22 μM。最后，分子对接分析揭示了JBP 485与OAT 1/3或DHP-I之间的直接相互作用。总之，JBP 485通过同时抑制肾OAT和DHP-I，改善IMP稳定性并减少其细胞内蓄积，从而保护兔和HK-2细胞免受IMP肾毒性。JBP 485是一种有前途的肾脏保护剂，可作为临床环境中减少IMP诱导的不良肾脏反应的有效补充剂。
Imipenem (IMP) possesses a broad spectrum of antibacterial activity; however, nephrotoxicity limits its clinical application in patients with renal insufficiency. In our previous studies, a dipeptide, JBP485, a dipeptide with the chemical structure cyclo-trans-4-L-hydroxyprolyl-L-serine, was found to attenuate drug-induced kidney injury. The current study aimed to explore whether JBP485 could relieve IMP-induced kidney injury and clarify the potential molecular pharmacokinetic mechanism. The effects of JBP485 on IMP nephrotoxicity were evaluated in rabbits and human kidney 2 (HK-2) cells. Drug-drug interactions (DDIs) mediated by organic anion transporters (OATs) and dehydropeptidase-I (DHP-I) were explored through pharmacokinetic studies in rats, metabolism assays in the kidney, and uptake studies in OAT-over-expressing cells. The results revealed that JBP485 significantly ameliorated IMP-induced nephrotoxicity in rabbits. Further, incubation of HK-2 cells with JBP485 or cilastatin markedly improved the cell survival rate, inhibited apoptosis and attenuated mitochondrial damage by improving the stability of IMP and reducing its intracellular accumulation. This suggests that DHP-I and OATs might be involved in the protective effect of JBP485. Furthermore, coadministration with JBP485 significantly increased the IMP’s plasma concentration as well as the area under the plasma concentration-time curve (AUC), while decreasing IMP renal clearance and cumulative urinary excretion. Moreover, JBP485 reduced IMP uptake in kidney slices and OAT1/3-human embryonic kidney 293 (HEK293) cells. At the same time, the metabolism of IMP by DHP-I was inhibited by JBP485 with an IC50 value of 12.15 ± 1.22 μM. Finally, the molecular docking assay revealed a direct interaction between JBP485 and OAT1/3 or DHP-I. In conclusion, JBP485 protected against IMP nephrotoxicity in rabbits and HK-2 cells by improving IMP stability and reducing its intracellular accumulation via simultaneous inhibition of renal OATs and DHP-I. JBP485 is a promising renoprotective agent and could serve as an effective supplement to reduce IMP-induced adverse renal reactions in the clinical setting.
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影响因子：
19.6
作者：
Motojima, M;Hosokawa, A;Yoshioka, T
通讯作者：
Yoshioka, T
影响因子：
4.6
作者：
Nagata M;Nakamura T;Hata Y;Yamaguchi S;Kaku T;Kinoshita S
通讯作者：
Kinoshita S
PEPT1 在体外和体内对 JBP485 的摄取、运输和调节
影响因子：
3
作者：
Liu, Zhihao;Wang, Changyuan;Liu, Kexin
通讯作者：
Liu, Kexin
影响因子：
6.5
作者：
Moreno-Gordaliza, Estefania;Esteban-Fernandez, Diego;Milagros Gomez-Gomez, M.
通讯作者：
Milagros Gomez-Gomez, M.
DOI：
10.1124/jpet.110.165779
发表时间：
2010-08-10
影响因子：
3.5
作者：
Camano, Sonia;Lazaro, Alberto;Tejedor, Alberto
通讯作者：
Tejedor, Alberto