Induction of B7-1 in podocytes is associated with nephrotic syndrome
Induction of B7-1 in podocytes is associated with nephrotic syndrome
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DOI：
10.1172/jci200420402
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发表时间：
2004-05-01
影响因子：
15.9
通讯作者：
Mundel, P
中科院分区：
文献类型：
--
作者：
Reiser, J;von Gersdorff, G;Mundel, P
肾足细胞和它们的裂孔隔膜形成了尿蛋白丢失的最后屏障。这解释了为什么足细胞损伤通常与肾病综合征相关。本研究揭示了共刺激分子B7-1在足细胞中作为肾小球通透性选择性的诱导修饰剂的一种意想不到的新作用。在遗传、药物诱导、免疫介导和细菌毒素诱导的肾病综合征实验性肾病中发现足细胞中的B7-1。足细胞B7-1表达与人类狼疮性肾炎的严重程度相关，这一观察结果强调了我们研究结果的临床意义。在体内，暴露于低剂量LPS迅速上调WT和SCID小鼠足细胞中的B7-1，导致肾病范围的蛋白尿。缺乏B7-1的小鼠免受LPS诱导的肾病综合征的影响，这表明足细胞B7-1表达与蛋白尿之间存在联系。LPS信号通过Toll样受体-4重组足细胞肌动蛋白细胞骨架在体外，并激活B7-1在培养的足细胞导致重组的重要狭缝隔膜蛋白。总之，足细胞中B7-1的上调可能通过破坏肾小球滤过器而促进蛋白尿的发病机制，并为解决蛋白尿性肾病提供了新的分子靶点。我们的研究结果表明，B7-1在非免疫细胞的危险信号中具有新的功能。
Kidney podocytes and their slit diaphragms form the final barrier to urinary protein loss. This explains why podocyte injury is typically associated with nephrotic syndrome. The present study uncovered an unanticipated novel role for costimulatory molecule B7-1 in podocytes as an inducible modifier of glomerular permselectivity. B7-1 in podocytes was found in genetic, drug-induced, immune-mediated, and bacterial toxin-induced experimental kidney diseases with nephrotic syndrome. The clinical significance of our results is underscored by the observation that podocyte expression of B7-1 correlated with the severity of human lupus nephritis. In vivo, exposure to low-dose LPS rapidly upregulates B7-1 in podocytes of WT and SCID mice, leading to nephrotic-range proteinuria. Mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, suggesting a link between podocyte B7-1 expression and proteinuria. LPS signaling through toll-like receptor-4 reorganized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes led to reorganization of vital slit diaphragm proteins. In summary, upregulation of B7-1 in podocytes may contribute to the pathogenesis of proteinuria by disrupting the glomerular filter and provides a novel molecular target to tackle proteinuric kidney diseases. Our findings suggest a novel function for B7-1 in danger signaling by nonimmune cells.