The map kinase ERK regulates renal activity of cyclin-dependent kinase 2 in experimental glomerulonephritis
The map kinase ERK regulates renal activity of cyclin-dependent kinase 2 in experimental glomerulonephritis
复制标题
DOI：
10.1093/ndt/gfm428
复制
发表时间：
2007-12-01
影响因子：
6.1
通讯作者：
Ostendorf, Tammo
中科院分区：
文献类型：
--
作者：
Bokemeyer, Dirk;Panek, Darius;Ostendorf, Tammo
背景在体外，细胞外信号调节激酶（ERK）是多种刺激在细胞内的汇聚点，影响细胞周期。然而，ERK在体内细胞周期调控中的作用尚不清楚。为了解决这一问题，ERK激活激酶的药理学抑制剂（U 0126）在体外的系膜细胞（MC）和在体内的实验性肾小球肾炎（GN）中阻断ERK活性。在刺激的MC中，ERK的抑制降低了细胞周期蛋白依赖性激酶2（CDK 2）的磷酸化，CDK 2的活性和细胞周期蛋白E/A的表达，而CDK抑制剂p27（Kip 1）的表达下调受到抑制。在体内，在抗Thy 1.1 GN的急性期给予大鼠U 0126。我们以前表明，肾小球细胞增殖减少了67后，治疗与抑制剂相比，肾炎控制。现在，我们检测到肾病对照组肾脏CDK 2活性/磷酸化显著增加，ERK抑制显著且剂量依赖性降低。CDK 2激活伴随着肾脏细胞周期蛋白E/A表达的增加以及这些细胞周期蛋白与肾病对照中CDK 2结合的增强。这些变化被U 0126处理减弱。最后，我们注意到肾炎对照组中p27（KIP 1）蛋白的表达和CDK 2结合增加，而U 0126治疗组中p27蛋白的表达和CDK 2结合减少。我们的观察提供了第一个证据，ERK是一个细胞内调节肾CDK 2活性在体内的肾小球肾炎模型。
Background. In vitro, the extracellular signal-regulated kinase (ERK) is an intracellular convergence point of multiple stimuli, which affect the cell cycle. However, the role of ERK in cell cycle regulation in vivo is unknown.Methods. To address this issue, ERK activity was blocked both in vitro in mesangial cells (MC) and in vivo in experimental glomerulonephritis (GN) by a pharmacological inhibitor (U0126) of the ERK-activating kinase.Results. In stimulated MC, inhibition of ERK reduced cyclin-dependent kinase 2 (CDK2) phosphorylation, CDK2 activity and cyclin E/A expression, whereas downregulation of CDK inhibitor p27(Kip1) expression was inhibited. In vivo, U0126 was given to rats in the acute phase of anti-Thy 1.1 GN. We previously showed that glomerular cell proliferation was reduced by 67 upon treatment with the inhibitor compared to nephritic controls. Now, we detected a significant increase in renal CDK2-activity/phosphorylation in the nephritic controls, that was significantly and dose-dependently reduced by ERK inhibition. CDK2 activation was accompanied by an increase in renal expression of cyclins E/A and the enhanced binding of these cyclins to CDK2 in the nephritic controls. These changes were blunted by U0126 treatment. Finally, we noted an increased expression and CDK2-binding of p27(KIP1) protein in the nephritic controls which was decreased in U0126 treated rats.Conclusions. Our observations provide the first evidence that ERK is an intracellular regulator of renal CDK2 activity in vivo in a glomerulonephritis model.