Syndecan-4 ectodomain evokes mobilization of podocyte TRPC6 channels and their associated pathways: An essential role for integrin signaling
Syndecan-4 ectodomain evokes mobilization of podocyte TRPC6 channels and their associated pathways: An essential role for integrin signaling
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DOI：
10.1016/j.bbamcr.2015.07.011
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发表时间：
2015-10-01
影响因子：
5.1
通讯作者：
Dryer, Stuart E.
中科院分区：
文献类型：
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作者：
Kim, Eun Young;Roshanravan, Hila;Dryer, Stuart E.
足细胞TRPC6 通道与肾小球疾病有关。 Syndecan-4 (Sdc4) 是一种膜蛋白多糖，可被裂解释放出能够进行旁分泌和自分泌信号传导的可溶性胞外域。我们已经证实，Sdc4核心蛋白的过度表达会增加培养足细胞中TRPC6通道的表面丰度，而Sdc4敲除则具有相反的效果。暴露于可溶性 Sdc4 胞外域还增加了 TRPC6 的表面丰度，并增加了足细胞中二酰基甘油类似物引起的阳离子电流。 Sdc4 胞外域增加了活性氧 (ROS) 的产生，减少了 RhoA 的激活，增加了 Rac1 的激活，增加了 NFATc1 的核丰度，并增加了总 β3-整合素。 Sdc4 胞外域对细胞表面 TRPC6 的影响被 ROS 猝灭剂 TEMPOL 和 Rac1 抑制剂 NSC-23766 阻断，但不被钙调神经磷酸酶-NFATc1 信号传导的抑制所阻断。 Sdc4 核心蛋白与培养的足细胞中的 β3-整合素发生免疫共沉淀。此外，Sdc4 胞外域对 TRPC6、ROS 生成、Racl 和 RhoA 调节以及 NFATc1 激活的影响被西仑吉肽阻断，西仑吉肽是一种通过含 ay 整联蛋白的由外向内信号传导的选择性抑制剂。暴露于 TNF 或三名复发 FSGS 复发患者的血清中，足细胞 Sdc4 胞外域向周围介质的脱落增加。在用金属蛋白酶 ADAM17 处理足细胞或过度表达 Sdc4 核心蛋白后也观察到了这一点。在急性嘌呤霉素氨基核苷肾病期间，在大鼠尿液中检测到 Sdc4 胞外域浓度增加。本地产生的 Sdc4 可能在调节 TRPC6 通道中发挥作用，并可能有助于肾小球病理学。 (C) 2015 Elsevier B.V. 保留所有权利。
PodocyteTRPC6 channels have been implicated in glomerular diseases. Syndecan-4 (Sdc4) is a membrane proteoglycan that can be cleaved to release a soluble ectodomain capable of paracrine and autocrine signaling. We have confirmed that overexpression of Sdc4 core protein increases surface abundance of TRPC6 channels in cultured podocytes, whereas Sdc4 knockdown has the opposite effect. Exposure to soluble Sdc4 ectodomain also increased the surface abundance of TRPC6, and increased cationic currents evoked by a diacylglycerol analog in podocytes. Sdc4 ectodomain increased generation of reactive oxygen species (ROS), reduced activation of RhoA, increased activation of Rac1, increased nuclear abundance of NFATc1, and increased total beta 3-integrin. The effects of Sdc4 ectodomain on cell-surface TRPC6 were blocked by the ROS quencher TEMPOL, and by the Rac1 inhibitor NSC-23766, but were not blocked by inhibition of calcineurin-NFATc1 signaling. The Sdc4 core protein co-immunoprecipitates with beta 3-integrin in cultured podocytes. Moreover, effects of Sdc4 ectodomain on TRPC6, ROS generation, Racl and RhoA modulation, and NFATc1 activation were blocked by cilengitide, a selective inhibitor of outside-in signaling through ay-containing integrins. Exposure to TNF, or serum from three patients with recurrent FSGS in relapse, increased shedding of podocyte Sdc4 ectodomains into the surrounding medium. This was also observed after treating podocytes with the metalloproteinase ADAM17 or after overexpression of the Sdc4 core protein. Increased concentrations of Sdc4 ectodomain were detected in urine of rats during acute puromycin aminonucleoside nephrosis. Locally generated Sdc4 may play a role in regulating TRPC6 channels, and may contribute to glomerular pathology. (C) 2015 Elsevier B.V. All rights reserved.