ROCK1 Induces Endothelial-to-Mesenchymal Transition in Glomeruli to Aggravate Albuminuria in Diabetic Nephropathy.
ROCK1 Induces Endothelial-to-Mesenchymal Transition in Glomeruli to Aggravate Albuminuria in Diabetic Nephropathy.
复制标题
ROCK1 诱导肾小球内皮细胞向间质细胞转变，加重糖尿病肾病的蛋白尿
DOI：
10.1038/srep20304
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发表时间：
2016-02-04
影响因子：
4.6
通讯作者：
Lou T
中科院分区：
文献类型：
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作者：
Peng H;Li Y;Wang C;Zhang J;Chen Y;Chen W;Cao J;Wang Y;Hu Z;Lou T
内皮-间质转化（EndMT）可导致肾小球紧密连接丧失，这与蛋白尿有关。在此，我们评估了EndMT在糖尿病肾病（DN）蛋白尿发生中的作用。我们发现，EndMT发生在DN患者的肾小球内皮细胞中，表现为CD 31表达减少而α-SMA表达增加。db/db小鼠肾小球内皮细胞ROCK 1表达增加，CD 31阳性细胞减少。培养的肾小球内皮细胞（GEnCs）进行EndMT时，刺激30 mM葡萄糖和表现出增加的渗透性。同时，它们显示出更高的ROCK 1表达和激活。值得注意的是，ROCK 1的抑制在很大程度上阻止了EndMT和这种高糖条件下内皮渗透性的增加。相反，ROCK 1的过度表达诱导了这些变化。在体内研究发现，用ROCK 1抑制剂法舒地尔治疗db/db小鼠，显著抑制肾小球内皮中α-SMA的表达，并减少蛋白尿。因此，我们得出结论，ROCK 1是由高糖诱导的，它刺激EndMT，导致内皮通透性增加。抑制ROCK 1可能是预防DN中肾小球内皮功能障碍和蛋白尿的治疗策略。
Endothelial-to-mesenchymal transition (EndMT) can cause loss of tight junctions, which in glomeruli are associated with albuminuria. Here we evaluated the role of EndMT in the development of albuminuria in diabetic nephropathy (DN). We demonstrated that EndMT occurs in the glomerular endothelium of patients with DN, showing by a decrease in CD31 but an increase in α-SMA expression. In glomeruli ofdb/dbmice, there was an increased ROCK1 expression in the endothelium plus a decreased CD31-positive cells. Cultured glomerular endothelial cells (GEnCs) underwent EndMT when stimulated by 30 mM glucose and exhibited increased permeability. Meanwhile, they showed a higher ROCK1 expression and activation. Notably, inhibition of ROCK1 largely blocked EndMT and the increase in endothelial permeability under this high-glucose condition. In contrast, overexpression of ROCK1 induced these changes. Consistent alterations were observedin vivothat treatingdb/dbmice with the ROCK1 inhibitor, fasudil, substantially suppressed the expression of α-SMA in the glomerular endothelium and reduced albuminuria. Thus we conclude that ROCK1 is induced by high glucose and it stimulates EndMT, resulting in increased endothelial permeability. Inhibition of ROCK1 could be a therapeutic strategy for preventing glomerular endothelial dysfunction and albuminuria in developing DN.