Detection of maleate-induced Fanconi syndrome by decreasing accumulation of 125I-3-iodo-α-methyl-L-tyrosine in the proximal tubule segment-1 region of renal cortex in mice:: a trial of separate evaluation of reabsorption
Detection of maleate-induced Fanconi syndrome by decreasing accumulation of 125I-3-iodo-α-methyl-L-tyrosine in the proximal tubule segment-1 region of renal cortex in mice:: a trial of separate evaluation of reabsorption
复制标题
DOI：
10.1007/bf03027427
复制
发表时间：
2006-04-01
影响因子：
2.6
通讯作者：
Kawai, K
中科院分区：
文献类型：
--
作者：
Shikano, N;Nakajima, S;Kawai, K
目的：Fanconi综合征是一种以多种组合的肾小管转运功能障碍为特征的肾功能障碍，涉及氨基酸、葡萄糖、蛋白质等物质。氨基酸的重吸收主要发生在近端肾小管段1(S1)。本研究基于肾皮质S1区氨基酸转运标志物I-125-3-碘-α-甲基-L酪氨酸(I-125-IMT)蓄积减少，评价了早期发现药物所致Fanconi综合征的可能性。本实验采用马来酸(MAL)诱导的小鼠Fanconi综合征模型。将I-125-IMT与其他3种临床肾放射性药物的结果进行了比较：TC-99m-2，3-二硫代丁二酸(TC-99m-DMSA)、TC-99m-巯基乙酰-甘氨酰甘氨酸(TC-99m-MAG(3))和TC-99m-二乙三胺五乙酸(TC-99m-DTPA)。方法：雄性ddy小鼠(6周龄，体重25g)复制Fanconi肾功能不全模型。单次腹腔注射马来酸二钠(6 mm o l/kg)。分别于注射MAL后30、60、90、120min行肾皮质苏木精-伊红(HE)染色、肾放射自显影及肾放射性测定。在注射标记化合物(蓄积实验18.5kBq，放射自显影670kBq)后5min，以乙醚过量处死动物，取肾脏。在累积实验中，使用井型闪烁计数器测量放射性。在放射自显影方面，用Bio-Image Analyzer制作了20 mm厚的冰冻肾脏切片。结果：注射MAL后30min，HE染色可见近端肾小管部分细胞固缩。当时，I-125-IMT和Tc-99m-DMSA在S1区域的累积约为对照水平的67%和55%(p<；0.005)。MAL可增加~(99)Tc-DTPA在S1区的蓄积，但不影响~(99)Tc-MAG(3)在S1区的蓄积。结论：I-123-IMT在S1区积聚减少可作为检测MAL诱导的Fanconi综合征的有用标志物。在未来，我们计划评估使用I-125-IMT监测肾毒性临床药物所致肾功能障碍的效果。
Objective: 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 I-125-3-iodo-alpha-methyl-L-tyrosine (I-125-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 I-125-IMT and 3 other clinical renal radiopharmaceuticals: Tc-99m-2,3-dimercaptosuccinic acid (Tc-99m-DMSA); Tc-99m-mercaptoacetyl-glycylglycylglycine (Tc-99m-MAG(3)); and Tc-99m-diethylenetriaminepentaacetic acid (Tc-99m-DTPA). Methods: 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-mu m sections of frozen kidney were used with Bio-Imaging Analyzer. Results: At 30 min after MAL injection, HE staining showed pyknosis in some proximal tubule cells. At that time, accumulations of I-125-IMT and Tc-99m-DMSA in the S1 region were approximately 67% and 55% of control levels (p < 0.005). MAL increased accumulation of Tc-99m-DTPA in the S1 region, but had no effect on accumulation of Tc-99m-MAG(3) in the S1 region. Conclusions: Decreased accumulation of I-123-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 I-125-IMT to monitor renal dysfunction induced by nephrotoxic clinical drugs.