Aberrantly glycosylated IgA1 induces mesangial cells to produce platelet-activating factor that mediates nephrin loss in cultured podocytes
Aberrantly glycosylated IgA1 induces mesangial cells to produce platelet-activating factor that mediates nephrin loss in cultured podocytes
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DOI：
10.1038/ki.2009.473
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发表时间：
2010-03-01
影响因子：
19.6
通讯作者：
Camussi, Giovanni
中科院分区：
文献类型：
--
作者：
Coppo, Rosanna;Fonsato, Valentina;Camussi, Giovanni
系膜细胞与异常糖基化的IgA1的反应与IgA肾病（IgAN）的病因有关。肿瘤坏死因子被认为介导系膜细胞和足细胞之间的相互作用，也诱导血小板活化因子（PAF）的表达。在这项研究中，我们确定了PAF是否影响足细胞中肾素（一种对肾小球过选择性至关重要的粘附分子）和细胞骨架f -肌动蛋白的表达。我们用体外制备的非典型糖基化IgA1或从IgAN患者血清中提取的IgA1处理人系膜细胞。然后我们从这些细胞中制备条件培养基，并在PAF受体拮抗剂存在的情况下将其加入培养的人足细胞中。转染过表达PAF主要分解代谢酶乙酰水解酶的足细胞作为对照。当足细胞在系膜细胞条件培养基中培养时，肾素表达下调和f -肌动蛋白重组发生。用PAF受体拮抗剂预孵育足细胞可防止肾素的丢失和重新分配。在过表达乙酰水解酶的足细胞中，肾素的损失被消除。我们的研究结果表明，来自系膜细胞的非典型糖基化iga诱导的PAF是足细胞变化的介质，当在其他地方进行更直接的测试时，发现与蛋白尿有关。因此，这些体外研究结果可能与IgAN的蛋白尿有关。肾脏国际（2010）77,417-427；doi: 10.1038 / ki.2009.473;2009年12月16日在线发布
The reaction of mesangial cells with aberrantly glycosylated IgA1 has been implicated in the etiology of IgA nephropathy (IgAN). Tumor necrosis factor, which is assumed to mediate the interaction between mesangial cells and podocytes, also induces the expression of platelet-activating factor (PAF). In this study, we determined whether PAF affects the expression of nephrin (an adhesion molecule critical to glomerular permselectivity) and cytoskeletal F-actin organization in podocytes. We treated human mesangial cells with atypically glycosylated IgA1 either prepared in vitro or derived from the sera of patients with IgAN. We then prepared conditioned media from these cells and added them to cultured human podocytes in the presence of PAF receptor antagonists. Podocytes transfected to overexpress acetylhydrolase, the main catabolic enzyme of PAF, served as controls. Downregulation of nephrin expression and F-actin reorganization occurred when podocytes were cultured with mesangial cell-conditioned medium. Preincubation of podocytes with a PAF receptor antagonist prevented the loss and redistribution of nephrin. In control podocytes overexpressing acetylhydrolase, nephrin loss was abrogated. Our results suggest that atypically glycosylated IgA-induced PAF from mesangial cells is a mediator of podocyte changes, which, when more directly tested elsewhere, were found to be associated with proteinuria. Hence, it is possible that these in vitro findings may be relevant to the proteinuria of IgAN. Kidney International (2010) 77, 417-427; doi:10.1038/ki.2009.473; published online 16 December 2009