Cyclosporine A protects podocytes by regulating WAVE1 phosphorylation.
Cyclosporine A protects podocytes by regulating WAVE1 phosphorylation.
复制标题
环孢素 A 通过调节 WAVE1 磷酸化保护足细胞
DOI：
10.1038/srep17694
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发表时间：
2015-12-04
影响因子：
4.6
通讯作者：
Ding J
中科院分区：
文献类型：
--
作者：
Li X;Ding F;Wang S;Li B;Ding J
越来越多的证据表明，足细胞是许多经典抗蛋白尿药物的直接靶点。免疫抑制药物环孢素A（CsA）是一种钙调神经磷酸酶抑制剂，用于治疗蛋白尿性肾病。CsA减少蛋白尿的一种新机制是直接稳定足细胞骨架。先前的研究表明，钙调神经磷酸酶可以直接调节小鼠纹状体切片中的WAVE 1。在这项研究中，WAVE 1在足细胞中表达，并定位于足细胞胞体和足突（FP）。WAVE 1表达在嘌呤霉素氨基糖苷（PAN）诱导的足细胞损伤的体内和体外模型中均增加。CsA恢复了PAN损伤后WAVE 1的表达，也部分挽救了PAN损伤后紊乱的F-actin排列。免疫共沉淀实验表明，钙调神经磷酸酶直接与WAVE 1相互作用，并调节WAVE 1在足细胞中的磷酸化。突触足蛋白是CsA的一个很好的特征性靶点。WAVE 1过表达和synaptopodin敲低实验直接证明WAVE 1表达不依赖于synaptopodin表达，反之亦然。与空载体组相比，使用WAVE 1质粒过表达WAVE 1破坏F-肌动蛋白结构并促进足细胞迁移。因此，WAVE 1可能是一个新的分子靶点，为足细胞FP的维护和抗蛋白尿治疗的未来。
Accumulating evidence suggests that podocytes are direct targets of many classic antiproteinuric drugs. The immunosuppressive drug cyclosporine A (CsA), which is a calcineurin inhibitor, is used to treat proteinuric kidney diseases. One novel mechanism by which CsA reduces proteinuria is by directly stabilizing the podocyte cytoskeleton. Previous studies showed that calcineurin can directly regulate WAVE1 within mouse striatal slices. In this study, WAVE1 was expressed in podocytes and was localized in the podocyte cell bodies and foot processes (FPs). WAVE1 expression increased in bothin vivoandin vitromodels of puromycin aminonucleoside (PAN)-induced podocyte injury. CsA restored WAVE1 expression and also partially rescued the disordered F-actin arrangement after PAN injury. Co-immunoprecipitation assays showed that calcineurin directly interacted with WAVE1 and regulated WAVE1 phosphorylation in podocytes. Synaptopodin is a well-characterized target of CsA. WAVE1 overexpression and synaptopodin knockdown experiments directly demonstrated that WAVE1 expression is not dependent on synaptopodin expression and vice versa. Overexpression of WAVE1 using a WAVE1 plasmid disrupted F-actin structure and promoted podocyte migration compared with the empty vector group. Therefore, WAVE1 may be a novel molecular target for the maintenance of podocyte FPs and for antiproteinuric treatment in the future.