Simvastatin alleviates hyperpermeability of glomerular endothelial cells in early-stage diabetic nephropathy by inhibition of RhoA/ROCK1.
Simvastatin alleviates hyperpermeability of glomerular endothelial cells in early-stage diabetic nephropathy by inhibition of RhoA/ROCK1.
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DOI：
10.1371/journal.pone.0080009
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lou T
中科院分区：
文献类型：
--
作者：
Peng H;Luo P;Li Y;Wang C;Liu X;Ye Z;Li C;Lou T
内皮功能障碍是糖尿病心血管疾病的早期征兆，并可能导致进行性糖尿病肾病（DN）。越来越多的证据表明，内皮紧密连接功能障碍是内皮细胞通透性增高的关键步骤，但尚不清楚这是否发生在DN进展过程中的肾小球内皮细胞（GEnCs）。我们研究了在早期DN期间GEnCs的紧密连接功能障碍及其潜在的潜在机制。我们还研究了辛伐他汀（3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂）对培养的GEnCs和早期DN db/db小鼠紧密连接功能障碍的影响。我们评估了紧密连接复合物的两个主要成分occludin和ZO-1在高糖处理的培养大鼠GEnCs和12周龄早期DN db/db小鼠中的表达。我们还研究了RhoA/ROCK 1信号转导，GEnC渗透性和小鼠肾功能的激活。高糖抑制GEnC中闭合蛋白表达并破坏闭合蛋白/ZO-1易位。这些变化与白蛋白渗透性增加和RhoA/ROCK 1信号转导激活有关。在早期DN小鼠肾小球中也出现了Occludin和ZO-1的失调，这些异常伴随着蛋白尿和孤立肾小球中RhoA/ROCK 1的激活。辛伐他汀通过抑制RhoA/ROCK 1信号通路来预防高糖或高血糖诱导的occludin和ZO-1的失调。我们的研究结果表明，高糖激活RhoA/ROCK 1破坏了occludin/ZO-1的表达和转位，辛伐他汀通过抑制RhoA/ROCK 1信号通路，在早期DN中抑制occludin/ZO-1的失调和蛋白尿。这些结果表明，一个潜在的治疗策略，以防止蛋白尿的发生在早期DN。
Endothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy (DN). There is increasing evidence that dysfunction of the endothelial tight junction is a crucial step in the development of endothelial hyperpermeability, but it is unknown whether this occurs in glomerular endothelial cells (GEnCs) during the progression of DN. We examined tight junction dysfunction of GEnCs during early-stage DN and the potential underlying mechanisms. We also examined the effect of simvastatin (3-Hydroxy-3-methylglutaryl CoA reductase inhibitor) on dysfunction of the tight junctions of cultured GEnCs and in db/db mice with early-stage DN. We assessed the expression of occludin and ZO-1, two major components of the tight junction complex, in cultured rat GEnCs treated with high glucose and in 12 week-old db/db mice with early-stage DN. We also investigated activation of RhoA/ROCK1 signaling, GEnC permeability, and renal function of the mice. High glucose suppresses occludin expression and disrupts occludin/ZO-1 translocation in GEnCs. These changes were associated with increased permeability to albumin and activation of RhoA/ROCK1 signaling. Occludin and ZO-1 dysregulation also occurred in the glomeruli of mice with early-stage DN, and these abnormalities were accompanied by albuminuria and activation of RhoA/ROCK1 in isolated glomeruli. Simvastatin prevented high glucose or hyperglycemia-induced dysregulation of occludin and ZO-1 by inhibition of RhoA/ROCK1 signaling in cultured GEnCs and in db/db mice with early-stage DN. Our results indicate that activation of RhoA/ROCK1 by high glucose disrupts the expression and translocation of occludin/ZO-1 and that simvastatin alleviates occludin/ZO-1 dysregulation and albuminuria by suppressing RhoA/ROCK1 signaling during early-stage DN. These results suggest a potential therapeutic strategy for preventing the onset of albuminuria in early-stage DN.
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