Role of c-Abl and nephrin in podocyte cytoskeletal remodeling induced by angiotensin II.
Role of c-Abl and nephrin in podocyte cytoskeletal remodeling induced by angiotensin II.
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c-Abl和去氧肾上腺素在血管紧张素II诱导的足细胞骨架重塑中的作用
DOI：
10.1038/s41419-017-0225-y
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发表时间：
2018-02-07
影响因子：
9
通讯作者：
Ding G
中科院分区：
文献类型：
--
作者：
Ma Y;Yang Q;Zhong Z;Liang W;Zhang L;Yang Y;Ding G
我们前期的研究表明，在体内外足细胞损伤的过程中，血管紧张素II（angiotensin II，Ang II）暴露可减弱nephrin与c-Abl之间的相互作用，进而减弱c-Abl介导的SHIP 2-Akt通路。然而，nephrin和c-Abl之间的关系尚不清楚。最近，各种研究表明nephrin是肾小球足细胞骨架重塑所必需的。但其具体机制仍不完全清楚。c-Abl作为一种参与细胞骨架调节的非受体酪氨酸激酶，可能是与nephrin的Src同源2/3（SH 2/SH 3）结构域相互作用的信号蛋白的候选者。因此，有人提出，c-Abl有助于肾蛋白依赖的足细胞的细胞骨架重塑。在此，我们观察到肾蛋白-c-Abl共定位在蛋白尿患者的肾小球中受到抑制。接下来，构建了CD 16/7-nephrin和c-Abl载体，以研究nephrin-c-Abl信号通路在足细胞肌动蛋白-细胞骨架重塑中的作用。通过与磷酸化的CD 16/7-nephrin和c-Abl全长构建体共转染，COS 7细胞中细胞松弛素D刺激的紊乱的细胞骨架显著恢复。免疫共沉淀结果显示，磷酸化的CD 16/7 nephrin与野生型c-Abl相互作用，而与SH 2/SH 3缺陷型c-Abl不相互作用，提示磷酸化nephrin能够以SH 2/SH 3依赖的方式募集c-Abl，并使c-Abl与去磷酸化nephrin分离，从而促进足细胞骨架的重塑。
Our previous study showed that angiotensin II (Ang II) exposure diminished the interaction between nephrin and c-Abl, then c-Abl mediated SHIP2-Akt pathway in the process of podocyte injury in vivo and vitro. However, the relationship between nephrin and c-Abl was unknown. Recently, various studies showed that nephrin was required for cytoskeletal remodeling in glomerular podocytes. But its specific mechanisms remain incompletely understood. As a nonreceptor tyrosine kinase involved in cytoskeletal regulation, c-Abl may be a candidate of signaling proteins interacting with Src homology 2/3 (SH2/SH3) domains of nephrin. Therefore, it is proposed that c-Abl contributes to nephrin-dependent cytoskeletal remodeling of podocytes. Herein, we observed that nephrin-c-Abl colocalization were suppressed in glomeruli of patients with proteinuria. Next, CD16/7-nephrin and c-Abl vectors were constructed to investigate the nephrin-c-Abl signaling pathway in podocyte actin-cytoskeletal remodeling. The disorganized cytoskeleton stimulated by cytochalasin D in COS7 cells was dramatically restored by co-transfection with phosphorylated CD16/7-nephrin and c-Abl full-length constructs. Further, co-immunoprecipitation showed that phosphorylated CD16/7-nephrin interacted with wild-type c-Abl, but not with SH2/SH3-defective c-Abl. These findings suggest that phosphorylated nephrin is able to recruit c-Abl in a SH2/SH3-dependent manner and detached c-Abl from dephosphorylated nephrin contributes to cytoskeletal remodeling in podocytes.
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