Localisation and mechanism of renal retention of radiolabelled somatostatin analogues
Localisation and mechanism of renal retention of radiolabelled somatostatin analogues
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DOI：
10.1007/s00259-005-1793-0
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发表时间：
2005-10-01
影响因子：
9.1
通讯作者：
de Jong, M
中科院分区：
文献类型：
--
作者：
Melis, M;Krenning, EP;de Jong, M
目的：放射标记的生长抑素类似物，如奥曲肽和奥曲酸酯，用于肿瘤显像和放射治疗。由于放射性标记肽的重吸收和保留，肾脏是这种治疗中最重要的关键器官。本研究的目的是在大鼠模型中研究静脉注射放射性标记生长抑素类似物后肾脏摄取的定位和机制。多配体meggalin /cubilin受体复合物负责肾脏中许多肽和蛋白质的重吸收，是这些肽类似物肾内吞作用的有趣候选物。方法：采用放射标记生长抑素类似物注射后1 ~ 24 h对大鼠肾脏进行离体放射自显影和显微放射自显影，并与肾脏抗巨噬细胞激素免疫组化染色模式进行比较。为了证实百高苷在奥曲肽[in -111\-DTPA]肾潴留机制中的作用，我们在大鼠身上研究了三种抑制物质的作用。结果：肾离体放射自显像显示肾皮质放射性高，外髓质放射性低。皮质放射性分布不均匀。显微放射自显像显示放射性仅保留在近端小管。抗meggalin免疫组织化学染色模式显示与肾[In-111-DTPA]奥曲肽离体x线片高度相似。生物分布研究表明，同时注射带正电荷的d -赖氨酸使肾脏摄取减少到对照组的60%。马来酸钠使肾脏[In-111-DTPA]奥曲肽摄取量降至对照组的15%。最后，顺铂预处理大鼠的肾脏摄取减少到对照组的70%。结论：[in- 111- dtpa]奥曲肽的肾潴留仅限于大鼠肾近端小管，其中巨噬蛋白介导的内吞作用可能起重要作用。
Purpose: Radiolabelled somatostatin analogues, such as octreotide and octreotate, are used for tumour scintigraphy and radionide therapy. The kidney is the most important critical organ during such therapy owing to the reabsorption and retention of radiolabelled peptides. The aim of this study was to investigate in a rat model both the localisation and the mechanism of renal uptake after intravenous injection of radiolabelled somatostatin analogues. The multi-ligand megalin/cubilin receptor complex, responsible for reabsorption of many peptides and proteins in the kidney, is an interesting candidate for renal endocytosis of these peptide analogues.Methods: For localisation studies, ex vivo autoradiography and micro-autoradiography of rat kidneys were performed 1 - 24 h after injection of radiolabelled somatostatin analogues and compared with the renal anti-megalin immunohistochemical staining pattern. To confirm a role of megalin in the mechanism of renal retention of [In-111\-DTPA] octreotide, the effects of three inhibitory substances were explored in rats.Results: Renal ex vivo autoradiography showed high cortical radioactivity and lower radioactivity in the outer medulla. The distribution of cortical radioactivity was inhomogeneous. Micro-autoradiography indicated that radioactivity was only retained in the proximal tubules. The antimegalin immunohistochemical staining pattern showed a strong similarity with the renal [In-111-DTPA] octreotide ex vivo autoradiograms. Biodistribution studies showed that co-injection of positively charged D-lysine reduced renal uptake to 60% of control. Sodium maleate reduced renal [In-111-DTPA] octreotide uptake to 15% of control. Finally, cisplatin pre-treatment of rats reduced kidney uptake to 70% of control.Conclusion: Renal retention of [In-111-DTPA] octreotide is confined to proximal tubules in the rat kidney, in which megalin-mediated endocytosis may play an important part.