NMDA receptors participate in the progression of diabetic kidney disease by decreasing Cdc42-GTP activation in podocytes.
NMDA receptors participate in the progression of diabetic kidney disease by decreasing Cdc42-GTP activation in podocytes.
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NMDA 受体通过减少足细胞中 Cdc42-GTP 的激活参与糖尿病肾病的进展。
DOI：
10.1002/path.4764
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
chen j
中科院分区：
文献类型：
--
作者：
shen j;wang r;he z;huang h;he x;zhou j;yan y;shen s;shao x;shen x;weng c;lin w;chen j
足细胞在糖尿病肾病（DKD）的进展中起重要作用，这些作用与细胞骨架肌动蛋白动力学密切相关。N -甲基- d -天冬氨酸受体（NMDARs）由两个功能性NR1亚基和两个调节性NR2亚基组成，在大脑中广泛表达，但也存在于足细胞中。在这里，我们发现NR1在两种糖尿病小鼠模型和高糖培养的足细胞中表达增加。在糖尿病小鼠中，使用携带NR1‐shRNA的慢病毒敲低NR1可改善与DKD相关的病理特征，并逆转synaptopodin和Wilms' tumor‐1的表达下降。在HG培养的足细胞中，NR1从内质网分泌，这被双吲哚酰亚胺i阻断。NR1的敲低降低了HG诱导的细胞形状重塑、细胞塌陷、牛血清白蛋白通透性和迁移。HG培养后，细胞分裂控制蛋白42 （Cdc42）及其活性形式的水平增加，Cdc42 - GTP水平显著升高，增加了Cdc42向前沿的易位。NR1敲低的足细胞迁移能力较低。NR1敲低的足细胞中丝状足的数量和长度增加，但用ML141阻断Cdc42 - GTP可消除这些增加。综上所述，NMDARs的激活通过降低Cdc42 - GTP的激活在DKD中发挥重要作用。版权所有©2016英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
Podocytes play important roles in the progression of diabetic kidney disease (DKD) and these roles are closely associated with cytoskeletal actin dynamics.N‐Methyl‐d‐aspartate receptors (NMDARs), which consist of two functional NR1 subunits and two regulatory NR2 subunits, are widely expressed in the brain but are also found in podocytes. Here, we found increased NR1 expression in two diabetic mouse models and in podocytes incubated in high glucose (HG). In diabetic mice, knockdown of NR1 using lentivirus carrying NR1‐shRNA ameliorated the pathological features associated with DKD, and reversed the decreased expression of synaptopodin and Wilms' tumour‐1. In podocytes incubated with HG, NR1 was secreted from the endoplasmic reticulum and this was blocked by bisindolylmaleimide I. NR1 knockdown decreased the cell shape remodelling, cell collapse, bovine serum albumin permeability, and migration induced by HG. After HG incubation, levels of cell division control protein 42 (Cdc42) and its active form increased, and a significantly higher Cdc42‐GTP level, increased Cdc42 translocation onto the leading edges, and lower migration ability were found in podocytes with NR1 knockdown. Increases in the number and length of filopodia were found in podocytes with NR1 knockdown but these were abolished by Cdc42‐GTP blockade with ML141. In conclusion, the activation of NMDARs plays an important role in DKD by reducing Cdc42‐GTP activation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.