Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria.
Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria.
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DOI：
10.1038/ki.2008.405
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发表时间：
2008-11
影响因子：
19.6
通讯作者：
Ichikawa, Iekuni
中科院分区：
文献类型：
--
作者：
Motoyoshi, Yaeko;Matsusaka, Taiji;Saito, Akihiko;Pastan, Ira;Willnow, Thomas E.;Mizutani, Shuki;Ichikawa, Iekuni
巨蛋白是否参与大分子大小的滤过蛋白的重吸收，并在此过程中促进肾小球疾病中肾小管损伤的发展，目前尚不确定。为了找到这些问题的答案，我们利用马赛克megalin敲除（KO）小鼠，其中缺乏megalin表达在60%的近端小管细胞（PTC），并进行非选择性蛋白尿的实验诱导。将Megalin KO小鼠与另一转基因系NEP 25交配。在后者中，肾小球损伤可由免疫毒素LMB 2诱导，LMB 2对足细胞上选择性表达的转基因产物具有特异性亲和力。向巨蛋白-KO/NEP 25小鼠（n=11）注射LMB 2。注射后10天，megalin-KO/NEP 25小鼠显示大量非选择性蛋白尿和轻度肾小球和肾小管损伤。比较每个巨蛋白KO/NEP 25小鼠肾脏内的巨蛋白完整（+）与缺陷（-）PTC，显示白蛋白、免疫球蛋白轻链、伊加和IgG优先在巨蛋白（+）PTC中积累。此外，肾小管损伤标志物，即血红素加氧酶-1，单核细胞趋化蛋白-1和凋亡，优先表达在megalin（+）PTC。这些结果共同表明，巨蛋白在小到大分子大小的蛋白质的重吸收中起着关键作用。该研究还提供了直接的体内证据，即过滤蛋白质的重吸收触发了可能导致肾小管损伤的事件。
It remains uncertain whether megalin participates in the reabsorption of filtered proteins with large molecular size and, in so doing, contributes to the development of tubule injury in glomerular diseases. To find answers to these questions, we utilized mosaic megalin knockout (KO) mice, which lack megalin expression in 60% of proximal tubule cells (PTCs), and were subjected to experimental induction of non-selective proteinuria. Megalin KO mice were mated with another transgenic line, NEP25. In the latter, glomerular injury can be induced by immunotoxin, LMB2, which has a specific affinity to a transgene product expressed selectively on podocytes. Megalin-KO/NEP25 mice (n=11) were injected with LMB2. Ten days after the injection, megalin-KO/NEP25 mice showed massive non-selective proteinuria and mild glomerular and tubular injury. Comparison of megalin-intact (+) vs. deficient (−) PTCs within each megalin-KO/NEP25 mouse kidney revealed that albumin, immunoglobulin light chain, IgA and IgG were preferentially accumulated in megalin (+) PTCs. Moreover, tubule injury markers, namely heme-oxygenase-1, monocyte chemoattractant protein-1 and apoptosis, were preferentially expressed in megalin (+) PTCs. These results collectively indicate that megalin plays a pivotal role in the reabsorption of small to large molecular size proteins. The study also provided direct in vivo evidence that reabsorption of filtered proteins triggers events that can lead to tubule injury.
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影响因子：
19.6
作者：
Kishore, BK;Krane, CM;Cacini, W
通讯作者：
Cacini, W
影响因子：
19.6
作者：
Ruggenenti, P;Perna, A;Remuzzi, G
通讯作者：
Remuzzi, G
影响因子：
6.1
作者：
Kriz, W;Hosser, H;Provoost, AP
通讯作者：
Provoost, AP
影响因子：
19.6
作者：
Kuusniemi, AM;Lapatto, R;Jalanko, H
通讯作者：
Jalanko, H
影响因子：
19.6
作者：
Bakoush, O;Grubb, A;Tencer, J
通讯作者：
Tencer, J