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Development of new methods for the evaluation and protection of drug induced nephrotoxicity using kidney epithelial cell line (LLC-PK_1)

开发利用肾上皮细胞系（LLC-PK_1）评估和保护药物引起的肾毒性的新方法

基本信息

批准号：
63870108
负责人：
HORI Ryohei
金额：
$ 4.35万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1989
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-63870108/
关键词：
Nephrotoxicity Cell Culture Cultured Renal Epithelial Cell Aminoglycoside Cyclosporin Cisplatin LLC-PK_1細胞

项目摘要

The kidney is a major organ for the excretion of xenobiotics, and is susceptible to drug-induced nephrotoxicity. We attempted to establish new methods for the evaluation and protection of nephrotoxicity of drugs by using a cultured kidney epithelial cell line, LLC-PK_1. Aminoglycoside antibiotics, cyclosporin (immunosuppressive agent), and cisplatin (antitumor agent) were employed in this study. These drugs are widely used clinically, but their use is sometimes complicated by acute nephrotoxicity.1. The effect of aminoglycoside, cyclosporin, and cisplatin was tested in LLC-PK_1 cells, and it was found that the number of viable cells, the number of floating cells (dead cells), the ability to form domes, and the activities of apical marker enzymes (aminopeptidase, alkaline phosphatase, and gamma-glutamyltransferase) are useful as markers of drug-induced cytotoxicity. There was a good relationship between the potencies of various aminoglycosides to inhibit apical enzymes in LLC-PK, cells … More and the nephrotoxic potencies of these drugs in vivo. In addition, aminoglycoside and cyclosporin induced the elevation of cytosolic free calcium concentration, which may be a important determinant of drug-induced nephrotoxicity.2. The inhibitory effect of gentamicin on the apical enzyme activities was dosedependent, and was related to its accumulation in the cells. Apparently, intracellular accumulation of cyclosporin was also related to its cytotoxicity, when judged by the level of cytosolic free calcium and the number of viable cells.3. Cytotoxicity of cisplatin was more potent on exponentially growing cells than on confluent cells. Glutathione attenuated the toxicity of cisplatin. In contrast, cyclosporin was toxic on growing and confluent cells, and glutathione had no effect on its cytotoxicity, indicating that biochemical mechanisms of nephrotoxicity are different among different drugs.In conclusion, cultured kidney epithelial cell line (LLC-PKi) should be a useful model system to evaluate the nephrotoxicity of drugs, and to develop a new method to protect the drug-induced nephrotoxicity. Less

肾脏是异生物质排泄的主要器官，容易受到药物引起的肾毒性的影响。我们尝试利用培养的肾上皮细胞系LLC-PK_1建立评估和保护药物肾毒性的新方法。本研究使用氨基糖苷类抗生素、环孢素（免疫抑制剂）和顺铂（抗肿瘤剂）。这些药物在临床上应用广泛，但有时会因急性肾毒性而使使用变得复杂。 1．在 LLC-PK_1 细胞中测试了氨基糖苷、环孢素和顺铂的作用，发现活细胞数、漂浮细胞（死细胞）数、形成圆顶的能力以及顶端标记酶（氨肽酶、碱性磷酸酶和 γ-谷氨酰转移酶）的活性可用作标记物药物诱导的细胞毒性。各种氨基糖苷类抑制 LLC-PK、细胞中顶端酶的效力与这些药物在体内的肾毒性效力之间存在良好的关系。此外，氨基糖苷类和环孢素可引起胞质游离钙浓度升高，这可能是药物肾毒性的重要决定因素。 2．庆大霉素对顶端酶活性的抑制作用呈剂量依赖性，并与其在细胞内的蓄积有关。显然，从胞质游离钙水平和活细胞数来判断，环孢素在细胞内的积累也与其细胞毒性有关。 3．顺铂对指数生长细胞的细胞毒性比对汇合细胞的细胞毒性更强。谷胱甘肽减弱顺铂的毒性。相比之下，环孢素对生长和汇合的细胞有毒性，而谷胱甘肽对其细胞毒性没有影响，这表明不同药物的肾毒性生化机制不同。总之，培养的肾上皮细胞系（LLC-PKi）应该是评估药物肾毒性的有用模型系统，并开发一种新的方法来保护肾毒性。药物引起的肾毒性。较少的