Investigative study of drug-induced nephropathy using renal cortical slice technique and cultured cell line

肾皮质切片技术和培养细胞系对药物性肾病的研究

• 批准号: 08671822
• 负责人: UOZUMI Jiro
• 金额: $ 1.47万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671822/
• 关键词: antibiotics; cisplatin; contrast medium; methylprednisolone; drug-induced nephropathy; NAG; gamma-GTP; renal cortical slice; イオン性造影剤; 非イオン性造影剤; r-GTP; 腎組織スライス; 抗癌剤

Experimental study to investigate the mechanism of prophylactic effect of methylprednisolone on cisplatin nephrotoxicity and clinical study to confirm the protective effects of methylprednisolone against cisplatin nephrotoxicity were conducted. Methylprednisolone induced increase in urinary platinum excretion, accompanied by a decrease in kidney platinum concentrations. The clinical usefulness of methylprednisolone against cisplatin nephrotoxicity were indicated.Renal cortical tissue prepared from rat and human were sliced and incubated with cefaloridine (CER) or gentamicin (GM) to examine the usefulness of renal cortical slice techniques. NAG was released from rat renal slice dose-dependently on CER concentration. Dose-related release of gamma-GTP from rat renal slice incubated with CER was not found. NAG release from human kidney tissue incubated with CER were less compared with that from rat kidney tissue. Human kidney tissue was less sensitive to CER nephrotoxicity. GM did not sign … More ificantly affect the enzyme release either from rat or human renal slice. This in vitro system is a simple and economical assay system to evaluate the drug-induced nephrotoxicity.The usefulness of renal cortical slice technique as an in vitro assay system to detect drug-induced nephrotoxicity was studied by evaluating the renal toxicity of cisplatin. Dose dependent increases of NAG, gamma-GTP, and LDH were observed. PAH accumulation in kidney slices was significantly reduced by cisplatin. Inhibitory effect of cisplatin on gluconeogenesis in renal slices was observed. These results suggested that toxic effect of cisplatin on renal epithelial cells was quantitatively determined by renal cortical slice technique. Renal cortical slice technique is a simple and economical in vitro assay system for evaluating cisplatin nephrotoxicity.To evaluate the contrast medium nephropathy, nephrotoxicity of low-osmolality contrast medium (LOOM) were examined in patients received radiographic studies using nonionic LOOM.Nephrotoxic effects of LOOM were compared with those of ionic high-osmolality contrast medium (HOOM) by renal cortical slice technique using rat renal tissue. Urinary NAG and gamma-GTP were sensitive indicators for contrast medium nephropathy. The clinical investigation suggested that nonionic LOOM injured renal tubular cells, while those renal damage can not be detected by serum creatinine or creatinine clearance. Renal cortical slice technique revealed that nonionic LOOM was as nephrotoxic as ionic HOCM. Less

本研究旨在探讨甲基强的松龙对顺铂肾毒性的预防作用机制，并进行临床研究以证实甲基强的松龙对顺铂肾毒性的保护作用。甲基强的松龙诱导尿铂排泄增加，伴随肾脏铂浓度降低。为探讨甲基强的松龙对顺铂肾毒性的临床疗效，制备大鼠和人肾皮质切片，分别与头孢洛定（CER）和庆大霉素（GM）孵育，观察肾皮质切片技术的有效性。NAG从大鼠肾片中的释放与CER浓度呈剂量依赖性。与CER孵育的大鼠肾组织相比，CER孵育的人肾组织中NAG的释放量明显减少。人肾组织对CER肾毒性的敏感性较低。通用汽车没有签署 ...更多信息 显著影响大鼠或人肾组织切片中酶的释放。本实验以顺铂的肾毒性为研究对象，探讨了肾皮质切片技术作为药物性肾毒性体外检测系统的可行性。观察到NAG、γ-GTP和LDH的剂量依赖性增加。顺铂可显著降低肾切片中PAH的蓄积。观察顺铂对肾片细胞凋亡的抑制作用。结果提示，肾皮质切片技术可定量测定顺铂对肾上皮细胞的毒性作用。肾皮质切片技术是评价顺铂肾毒性的一种简单、经济的体外实验系统，为了评价造影剂肾病，采用非离子型低渗造影剂（LOOM）对接受造影检查的患者进行肾毒性研究，并与离子型高渗造影剂（HOOM）进行肾皮质切片比较。尿NAG和γ-GTP是诊断造影剂肾病的敏感指标。临床研究表明，非离子型LOOM对肾小管细胞有损伤作用，而这种肾损害不能通过血肌酐或肌酐清除率来检测。肾皮质切片技术显示非离子型LOOM与离子型HOCM具有相同的肾毒性。少

项目成果

魚住二郎: "MVAC動注と全身投与におけるシスプラチン投与後の腎機能変化の比較検討" 西日泌尿. 59・5. 438-441 (1997)

鱼住二郎：“使用MVAC动脉内注射和全身给药的顺铂给药后肾功能变化的比较研究”Nishinichi Urinary Journal 59・5（1997）。

Uozumi J: "The evaluation of drug-induced nephrotoxicity using renal cortical slice obtained from rat and human" Brit J Urol. 80・suppl 2. 116 (1997)

Uozumi J：“使用从大鼠和人获得的肾皮质切片评估药物引起的肾毒性”Brit J Urol. 80·suppl 2. 116 (1997)

Jiro Uozumi et al: "The effect of methylprednisolone on platinum kinetics an urinary enzyme excretion following intravenous cisplatin in vivo and on the growth inhibition of LLC-PK1 cells by cisplatin in vitro" Res Exp Med. 196. 211-217 (1996)

Jiro Uozumi 等人：“甲基强的松龙对体内静脉注射顺铂后的铂动力学和尿酶排泄的影响，以及体外顺铂对 LLC-PK1 细胞生长抑制的影响”Res Exp Med。

Uozumi J,Kumazawa J,Nakamura M: "The evaluation of drug-induced nephrotoxicity using renal cortical slice obtained from rat and human." Brit J Urol. 80-suppl 2. 116 (1997)

Uozumi J、Kumazawa J、Nakamura M：“使用从大鼠和人类获得的肾皮质切片评估药物引起的肾毒性。”

Nakamura M,Uozumi J: "Renal corticl slice techniques for evaluating drug-induced nephrotoxicity in rat and human." Toxicol Letters. 95-suppl 1. 166 (1998)

Nakamura M，Uozumi J：“用于评估大鼠和人类药物引起的肾毒性的肾皮质切片技术。”