Shikano Naoto, Nakajima Syuichi, Kotani Takashi, Itoh Yusuke, Nishii Ryuichi, Yoshimoto Mitsuyoshi, Flores Leo Garcia, Saji Hideo, Ishikawa Nobuyoshi, Kawai Keiichi
Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan.
Ann Nucl Med. 2006 Apr;20(3):175-81. doi: 10.1007/BF03027427.
Fanconi syndrome is a renal dysfunction characterized by various combinations of renal tubular transport dysfunction involving amino acids, glucose, protein and other substances. Most reabsorption of amino acids occurs in proximal renal tubule segment 1 (S1). The present study evaluated the possibility of early detection of drug-induced Fanconi syndrome, based on decreased renal accumulation of 125I-3-iodo-alpha-methyl-L-tyrosine (125I-IMT), an amino acid transport marker, in the S1 region of renal cortex. The present experimental model used maleate (MAL)-induced Fanconi syndrome in mice. Results were compared between 125I-IMT and 3 other clinical renal radiopharmaceuticals: 99mTc-2,3-dimercaptosuccinic acid (99mTc-DMSA); 99mTc-mercaptoacetylglycylglycylglycine (99mTc-MAG3); and 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA).
Male ddY mice (age, 6 weeks; body weight, 25 g) were used to create a Fanconi model of renal dysfunction. A single dose of maleate disodium salt was administered by intraperitoneal injection (6 mmol/kg). Hematoxylin and eosin (HE) staining of the renal cortex, renal autoradiography and measurement of renal radioactivity of labeled compounds were performed at 30, 60, 90 and 120 min after MAL injection. At 5 min after injection of labeled compounds (18.5 kBq for accumulation experiment, 670 kBq for autoradiography), animals were sacrificed by ether overdose and kidneys were removed. For the accumulation experiment, radioactivity was measured using a well-type scintillation counter. For autoradiography, 20-microm sections of frozen kidney were used with Bio-Imaging Analyzer.
At 30 min after MAL injection, HE staining showed pyknosis in some proximal tubule cells. At that time, accumulations of 125I-IMT and 99mTc-DMSA in the S1 region were approximately 67% and 55% of control levels (p < 0.005). MAL increased accumulation of 99mTc-DTPA in the S1 region, but had no effect on accumulation of 99mTc-MAG3 in the S 1 region.
Decreased accumulation of 123I-IMT in the S1 region appears to represent a useful marker for detection of MAL-induced Fanconi syndrome. In future, we plan to assess the efficacy of using 125I-IMT to monitor renal dysfunction induced by nephrotoxic clinical drugs.
范科尼综合征是一种肾功能障碍，其特征是肾小管对氨基酸、葡萄糖、蛋白质及其他物质的转运功能出现各种组合的异常。氨基酸的重吸收大多发生在近端肾小管1段（S1）。本研究基于肾皮质S1区氨基酸转运标志物125I-3-碘-α-甲基-L-酪氨酸（125I-IMT）肾摄取减少，评估早期检测药物性范科尼综合征的可能性。本实验模型采用马来酸盐（MAL）诱导的小鼠范科尼综合征。将125I-IMT与其他3种临床肾放射性药物的结果进行比较：99mTc-2,3-二巯基丁二酸（99mTc-DMSA）；99mTc-巯基乙酰甘氨酰甘氨酰甘氨酸（99mTc-MAG3）；以及99mTc-二乙三胺五乙酸（99mTc-DTPA）。
雄性ddY小鼠（6周龄；体重25 g）用于建立肾功能障碍的范科尼模型。通过腹腔注射给予单剂量马来酸钠盐（6 mmol/kg）。在注射MAL后30、60、90和120分钟进行肾皮质苏木精-伊红（HE）染色、肾脏放射自显影及标记化合物的肾放射性测量。在注射标记化合物后5分钟（蓄积实验用18.5 kBq，放射自显影用670 kBq），通过过量乙醚处死动物并摘除肾脏。对于蓄积实验，使用井型闪烁计数器测量放射性。对于放射自显影，使用冰冻肾脏的20微米切片及生物成像分析仪。
注射MAL后30分钟，HE染色显示一些近端小管细胞出现核固缩。此时，S1区125I-IMT和99mTc-DMSA的蓄积量分别约为对照水平的67%和55%（p < 0.005）。MAL增加了S1区99mTc-DTPA的蓄积，但对S1区99mTc-MAG3的蓄积无影响。
S1区123I-IMT蓄积减少似乎是检测MAL诱导的范科尼综合征的有用标志物。未来，我们计划评估使用125I-IMT监测肾毒性临床药物所致肾功能障碍的疗效。
