Urinary megalin deficiency implicates abnormal tubular endocytic function in Fanconi syndrome
Urinary megalin deficiency implicates abnormal tubular endocytic function in Fanconi syndrome
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DOI：
10.1681/asn.v131125
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发表时间：
2002-01-01
影响因子：
13.6
通讯作者：
Moestrup, SK
中科院分区：
文献类型：
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作者：
Norden, AGW;Lapsley, M;Moestrup, SK
正常的肾小球滤液蛋白的重吸收可能需要内吞受体megalin(Gp330)和cubilin的再循环。两种受体均位于肾近端小管上皮细胞的管腔表面。探讨Dent病、Lowe‘s综合征或常染色体显性遗传性特发性Fanconi综合征患者的尿液中是否存在异常数量的受体。它们都是肾Fanconi综合征的形式，并与小管性蛋白尿有关。对等量肌酐的尿样进行透析、冷冻干燥，并在非还原十二烷基硫酸钠-5%聚丙烯酰胺凝胶上进行电泳。用抗megalin抗体、抗cubilin抗体或受体相关蛋白对蛋白质进行印迹和检测。免疫化学发光法检测的megalin和cubilin水平作为积分像素进行测量，并表示为正常平均值的百分比。9个Dent病家系中有8个家系(n=10)和2个Lowe‘s综合征家系(n=3)尿巨蛋白显著低于正常人(n=42)。常染色体显性遗传性特发性Fanconi综合征家系(n=2)的巨蛋白水平在正常范围内。所有患者测得的Cubilin水平均正常。这些结果与Dent‘s病和Lowe’s综合征患者近端小管顶端细胞表面的巨蛋白有缺陷的再循环，从而减少了尿中的丢失是一致的。这种缺陷会干扰巨蛋白的正常内吞功能，导致潜在的配体丢失进入尿液，并产生小管性蛋白尿。
Normal reabsorption of glomerular filtrate proteins probably requires recycling of the endocytic receptors megalin (gp330) and cubilin. Both receptors are located on the luminal surface of the renal proximal tubule epithelium. Whether abnormal amounts of receptor are present in the urine of patients with Dent's disease, Lowe's syndrome, or autosomal dominant idiopathic Fanconi syndrome was explored. They are all forms of the renal Fanconi syndrome and are associated with tubular proteinuria. Urine samples of equal creatinine contents were dialyzed, lyophilized, and subjected to electrophoresis on nonreducing sodium dodecyl sulfate-5% polyacrylamide gels. Proteins were blotted and probed with anti-megalin IgG, anti-cubilin IgG, or receptor-associated protein. Megalin and cubilin levels detected by immunochemiluminescence were measured as integrated pixels and expressed as percentages of the normal mean values. A striking deficiency of urinary megalin, compared with normal individuals (n = 42), was observed for eight of nine families with Dent's disease (n = 10) and for the two families with Lowe's syndrome (n = 3). The family with autosomal dominant idiopathic Fanconi syndrome (n = 2) exhibited megalin levels within the normal range. The measured levels of cubilin were normal for all patients. These results are consistent with defective recycling of megalin to the apical cell surface of the proximal tubules and thus decreased loss into urine in Dent's disease and Lowe's syndrome. This defect would interfere with the normal endocytic function of megalin, result in losses of potential ligands into the urine, and produce tubular proteinuria.