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首页> 外文期刊>Molecular and Cellular Biology >Shp2 Associates with and Enhances Nephrin Tyrosine Phosphorylation and Is Necessary for Foot Process Spreading in Mouse Models of Podocyte Injury
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Shp2 Associates with and Enhances Nephrin Tyrosine Phosphorylation and Is Necessary for Foot Process Spreading in Mouse Models of Podocyte Injury

机译：Shp2与并增强肾素酪氨酸磷酸化，是足细胞损伤在小鼠足细胞损伤模型中传播所必需的。

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In most forms of glomerular diseases, loss of size selectivity by the kidney filtration barrier is associated with changes in the morphology of podocytes. The kidney filtration barrier is comprised of the endothelial lining, the glomerular basement membrane, and the podocyte intercellular junction, or slit diaphragm. The cell adhesion proteins nephrin and neph1 localize to the slit diaphragm and transduce signals in a Src family kinase Fyn-mediated tyrosine phosphorylation-dependent manner. Studies in cell culture suggest nephrin phosphorylation-dependent signaling events are primarily involved in regulation of actin dynamics and lamellipodium formation. Nephrin phosphorylation is a proximal event that occurs both during development and following podocyte injury. We hypothesized that abrogation of nephrin phosphorylation following injury would prevent nephrin-dependent actin remodeling and foot process morphological changes. Utilizing a biased screening approach, we found nonreceptor Src homology 2 (sh2) domain-containing phosphatase Shp2 to be associated with phosphorylated nephrin. We observed an increase in nephrin tyrosine phosphorylation in the presence of Shp2 in cell culture studies. In the human glomerulopathies minimal-change nephrosis and membranous nephropathy, there is an increase in Shp2 phosphorylation, a marker of increased Shp2 activity. Mouse podocytes lacking Shp2 do not develop foot process spreading when subjected to podocyte injury in vivo using protamine sulfate or nephrotoxic serum (NTS). In the NTS model, we observed a lack of foot process spreading in mouse podocytes with Shp2 deleted and smaller amounts of proteinuria. Taken together, these results suggest that Shp2-dependent signaling events are necessary for changes in foot process structure and function following injury.
机译：在大多数形式的肾小球疾病中，肾脏滤过屏障丧失大小选择性与足细胞形态的变化有关。肾脏滤过屏障由内皮层，肾小球基底膜和足细胞胞间连接或裂隙膜组成。细胞粘附蛋白nephrin和neph1定位于缝隙隔膜并以Src家族激酶Fyn介导的酪氨酸磷酸化依赖性方式转导信号。细胞培养研究表明，肾素依赖磷酸化的信号转导事件主要参与肌动蛋白动力学和lamellipodium形成的调节。肾素磷酸化是在发育过程中和足细胞损伤后发生的近端事件。我们假设损伤后废除肾素磷酸化将阻止依赖于肾素的肌动蛋白重塑和脚突形态改变。利用偏倚的筛选方法，我们发现非受体Src同源2（sh2）域包含磷酸酶Shp2与磷酸化的肾素有关。我们在细胞培养研究中观察到在Shp2存在下肾素酪氨酸磷酸化的增加。在人类肾小球病微变肾病和膜性肾病中，Shp2磷酸化增加，这是Shp2活性增加的标志。缺少Shp2的小鼠足细胞在体内使用硫酸鱼精蛋白或肾毒性血清（NTS）遭受足细胞损伤时，不会发生足突扩散。在NTS模型中，我们观察到在Shp2缺失且蛋白尿量较少的小鼠足细胞中没有足突扩散。综上所述，这些结果表明，Shp2依赖性信号转导对于受伤后足突结构和功能的改变是必需的。

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