Protective effect of cilastatin against diclofenac-induced nephrotoxicity through interaction with diclofenac acyl glucuronide via organic anion transporters
Protective effect of cilastatin against diclofenac-induced nephrotoxicity through interaction with diclofenac acyl glucuronide via organic anion transporters
复制标题
西司他丁通过有机阴离子转运蛋白与双氯芬酸酰基葡萄糖醛酸苷相互作用对双氯芬酸诱导的肾毒性的保护作用
DOI：
10.1111/bph.14957
复制
发表时间：
2020-05-01
影响因子：
7.3
通讯作者：
Liu, Kexin
中科院分区：
文献类型：
--
作者：
Huo, Xiaokui;Meng, Qiang;Liu, Kexin
背景与目的双氯芬酸是一种应用广泛的非甾体类抗炎药。但其对肾脏的不良反应限制了其临床应用。本研究旨在评估西司他汀对双氯芬酸诱导的急性肾损伤的潜在影响，并阐明肾有机阴离子转运体（OATs）在西司他汀与双氯芬酸药物相互作用中的潜在作用。实验方法观察西司他汀对双氯芬酸致小鼠急性肾损伤的影响。采用转染人oat1 /3的HEK293细胞和肾原代近端小管细胞（RPTCs）研究oat1 /3介导的转运和双氯芬酸的细胞毒性。西司他汀治疗可减轻小鼠双氯芬酸所致的肾脏病理改变、肾功能损害、氧化产物水平升高、细胞因子产生和细胞凋亡。此外，西司他汀增加了双氯芬酸及其葡萄糖醛酸代谢产物双氯芬酸酰基葡萄糖醛酸（DLF-AG）的血浆浓度，降低了肾脏分布。同样，西司他汀抑制RPTCs的细胞毒性和线粒体损伤，但没有改变双氯芬酸的细胞内积聚。DLF-AG表现出oat依赖的细胞毒性，而双氯芬酸不表现出oat依赖的细胞毒性，并被鉴定为oat /3底物。西司他汀抑制RPTCs细胞内积累，降低DLF-AG的细胞毒性。结论及意义西司他汀可通过恢复氧化还原平衡、抑制炎症、减少细胞凋亡等途径减轻双氯芬酸所致小鼠急性肾损伤。西司他汀抑制OATs，降低双氯芬酸和DLF-AG的肾分布，进一步改善双氯芬酸所致小鼠肾毒性。西司他汀有可能作为一种治疗药物用于临床，以减轻双氯芬酸对肾脏的不良反应。
Background and Purpose Diclofenac is a widely used nonsteroidal anti-inflammatory drug. However, adverse effects in the kidney limit its clinical application. The present study was aimed to evaluate the potential effect of cilastatin on diclofenac-induced acute kidney injury and to clarify the potential roles of renal organic anion transporters (OATs) in the drug-drug interaction between cilastatin and diclofenac.Experimental Approach The effect of cilastatin was evaluated in diclofenac-induced acute kidney injury in mice. Human OAT1/3-transfected HEK293 cells and renal primary proximal tubule cells (RPTCs) were used to investigate OAT1/3-mediated transport and the cytotoxicity of diclofenac.Key Results Cilastatin treatment decreased the pathological changes, renal dysfunction and elevated renal levels of oxidation products, cytokine production and apoptosis induced by diclofenac in mice. Moreover, cilastatin increased the plasma concentration and decreased the renal distribution of diclofenac and its glucuronide metabolite, diclofenac acyl glucuronide (DLF-AG). Similarly, cilastatin inhibited cytotoxicity and mitochondrial damage in RPTCs but did not change the intracellular accumulation of diclofenac. DLF-AG but not diclofenac exhibited OAT-dependent cytotoxicity and was identified as an OAT1/3 substrate. Cilastatin inhibited the intracellular accumulation and decreased the cytotoxicity of DLF-AG in RPTCs.Conclusion and Implications Cilastatin alleviated diclofenac-induced acute kidney injury in mice by restoring the redox balance, suppressing inflammation, and reducing apoptosis. Cilastatin inhibited OATs and decreased the renal distribution of diclofenac and DLF-AG, which further ameliorated the diclofenac-induced nephrotoxicity in mice. Cilastatin can be potentially used in the clinic as a therapeutic agent to alleviate the adverse renal reaction to diclofenac.