Cubilin Is Essential for Albumin Reabsorption in the Renal Proximal Tubule
Cubilin Is Essential for Albumin Reabsorption in the Renal Proximal Tubule
复制标题
DOI：
10.1681/asn.2010050492
复制
发表时间：
2010-11-01
影响因子：
13.6
通讯作者：
Kozyraki, Renata
中科院分区：
文献类型：
--
作者：
Amsellem, Sabine;Gburek, Jakub;Kozyraki, Renata
受体介导的内吞作用负责近端小管中的蛋白质重吸收。该过程涉及两种相互作用的受体，megalin和cubilin，它们与cubilin形成复合物。这些蛋白质是否平行或作为整合系统的一部分起作用还不清楚。在此，我们报告了cubilin的遗传消融伴或不伴megalin消融的肾脏效应，使用条件性Cre loxP系统，我们观察到在不存在cubilin的情况下近端小管细胞不将cubilonless定位于质膜，这表明cubilin和cubilonless形成功能性膜受体复合物的相互依赖性。cubilin cubilonless复合物介导内在因子-维生素B12复合物的内化，但是巨蛋白显著增加了摄取此外，cubilin缺乏的小鼠表现出近端小管细胞对白蛋白的摄取显著降低，并且导致白蛋白尿。巨蛋白和cubilin的失活不增加白蛋白尿，表明巨蛋白在白蛋白重吸收中的主要作用是驱动cubilin-albumin复合物的内化。相反，cubulin缺乏并不影响肾小管吸收或排泄结合cubilin和megalin的维生素D-结合蛋白（DBP）。此外，我们观察到“特异性”cubilin配体转铁蛋白、CC 16和apoA-I的cubilin非依赖性重吸收，提示巨蛋白和可能的其他受体在其重吸收中的作用总之，关于白蛋白，cubilin对于其被近端小管细胞重吸收是必需的，并且巨蛋白驱动cubilin白蛋白复合物的内化。这些遗传模型将允许进一步分析蛋白尿性肾病进展中的蛋白运输。
Receptor-mediated endocytosis is responsible for protein reabsorption in the proximal tubule This process involves, two interacting receptors, megalin and cubilin which form a complex with amnionless Whether these proteins function in parallel or as part of an integrated system is not well understood Here we report the renal effects of genetic ablation of cubilin with or without concomitant ablation of megalin, using a conditional Cre loxP system We observed that proximal tubule cells did not localize amnionless to the plasma membrane in the absence of cubilin indicating a mutual dependency of cubilin and amnionless to form a functional membrane receptor complex The cubilin amnionless complex mediated internalization of intrinsic factor-vitamin B12 complexes, but megalin considerably increased the uptake Furthermore, cubilin-deficient mice exhibited markedly decreased uptake of albumin by proximal tubule cells and resultant albuminuria Inactivation of both megalin and cubilin did not increase albuminuria, indicating that the main role of megalin in albumin reabsorption is to drive the internalization of cubilin-albumin complexes In contrast, cubulin deficiency did not affect urinary tubular uptake or excretion of vitamin D-binding protein (DBP), which binds cubilin and megalin In addition, we observed cubilin-independent reabsorption of the "specific" cubilin ligands transferrin, CC16, and apoA-I, suggesting a role for megalin and perhaps other receptors in their reabsorption In summary, with regard to albumin, cubilin is essential for its reabsorption by proximal tubule cells, and megalin drives internalization of cubilin albumin complexes These genetic models will allow further analysis of protein trafficking in the progression of proteinuric renal diseases