The calcineurin-NFAT pathway allows for urokinase receptor-mediated beta3 integrin signaling to cause podocyte injury.
The calcineurin-NFAT pathway allows for urokinase receptor-mediated beta3 integrin signaling to cause podocyte injury.
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DOI：
10.1007/s00109-012-0960-6
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发表时间：
2012-12
影响因子：
4.7
通讯作者：
Wang, Wenjian
中科院分区：
文献类型：
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作者：
Zhang, Bin;Shi, Wei;Ma, Juan;Sloan, Alexis;Faul, Christian;Wei, Changli;Reiser, Jochen;Yang, Yun;Liu, Shuangxin;Wang, Wenjian
循环和足细胞结合尿激酶受体（uPAR）是足细胞损伤、蛋白尿和局灶节段性肾小球硬化（FSGS）的介质，可导致uPAR-β3整联蛋白信号传导轴的病理激活。临床上，钙调磷酸酶抑制剂（例如，环孢菌素A，CsA）已知抑制T细胞，但也用于减少FSGS中的蛋白尿，这表明uPAR和钙调磷酸酶之间的信号串扰的可能性。已知钙调磷酸酶促进活化T细胞核因子（NFAT）的核转位。因此，足细胞中的体内条件性NFATc 1激活导致小鼠蛋白尿，但NFAT的下游靶点仍不清楚。在这里，我们表明，诱导足细胞特异性表达的组成型活性NFATc 1增加足细胞uPAR的表达，通过结合到Plaur基因启动子（编码uPAR）在染色质免疫沉淀试验。足细胞中的病理性uPAR信号不依赖于T细胞，并通过活化而非表达影响细胞运动性，β3整联蛋白的变化，并且可以使用肾小球疾病的啮齿动物模型（LPS; 5/6肾切除大鼠）通过CsA、NFAT-siRNA或细胞可渗透的NFAT抑制剂（11 R-VIVIT）阻断。总之，这些发现确定足细胞uPAR作为NFAT的下游靶点，并为FSGS的发病机制提供了进一步的见解。
Circulating and podocyte-bound urokinase receptor (uPAR) is a mediator of podocyte injury, proteinuria, and focal segmental glomerulosclerosis (FSGS) allowing pathological activation of the uPAR-β3 integrin signaling axis. Clinically, calcineurin inhibitors (e.g., cyclosporine A, CsA) are known to suppress T cells, yet are also being used to reduce proteinuria in FSGS, suggesting the possibility of signal cross talk between uPAR and calcineurin. Calcineurin is known to facilitate the nuclear translocation of the nuclear factor of activated T cells (NFAT). Accordingly, in vivo conditional NFATc1 activation in podocytes leads to proteinuria in mice, yet the downstream targets of NFAT remain unclear. Here, we show that inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays. Pathological uPAR signals in podocytes are independent of T cells and affect cell motility via activation, but not expression, changes of the β3 integrin and can be blocked by CsA, NFAT-siRNA, or the cell-permeable NFAT inhibitor (11R-VIVIT) using rodent models of glomerular disease (LPS; 5/6 nephrectomized rats). Taken together, these findings identify podocyte uPAR as a downstream target of NFAT and provide further insights into the pathogenesis of FSGS.
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影响因子：
6.1
作者：
Amann, K;Nichols, C;Ritz, E
通讯作者：
Ritz, E
影响因子：
4.8
作者：
Reiser, J;Oh, J;Mundel, P
通讯作者：
Mundel, P
影响因子：
4.4
作者：
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Crabtree, Gerald R.
影响因子：
15.9
作者：
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通讯作者：
Reiser, Jochen
影响因子：
82.9
作者：
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