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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Glucose-induced endothelin-1 expression is regulated by ERK5 in the endothelial cells and retina of diabetic rats.
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Glucose-induced endothelin-1 expression is regulated by ERK5 in the endothelial cells and retina of diabetic rats.

机译:葡萄糖诱导的内皮素-1表达受糖尿病大鼠内皮细胞和视网膜中ERK5的调节。

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摘要

Upregulation of endothelin 1 (ET-1) causing blood flow alteration and increased extracellular matrix production are characteristic features of diabetic angiopathy. Several glucose-induced signaling mechanisms cause ET-1 upregulation in diabetic angiopathy. Extracellular signal-regulated kinase 5 (ERK5) is a member of the MAPK family, which plays a key role in cardiovascular development. ERK kinase (MEK) 5 is the specific MEK for ERK5 activation. In this study we examined the role of glucose-induced ERK5 signaling in mediating ET-1 expression in diabetic angiopathy. We investigated retinas from 1-month STZ-induced diabetic rats and human macro- and microvascular endothelial cells to study ERK5-dependent ET-1 alterations. Glucose (25 mmol/L) caused significant upregulation of ET-1 mRNA and downregulation of ERK5 and Kruppel-like factor 2 (KLF2) after 24 h treatment in the endothelial cells. Simultaneously, phospho-ERK5 proteins were reduced. Activation of ERK5 by constitutively active MEK5 (caMEK5) upregulated KLF2 and suppressed ET-1 expression in both cell lines, whereas ERK5 siRNA transfection resulted in decreased ERK5 and KLF2 and increased ET-1 mRNA expression. In addition, caMEK5 prevented glucose-induced upregulation of ET-1. Furthermore, 1 month of diabetes caused a significant increase in retinal ET-1 mRNA and decrease in ERK5 mRNA expression. These data indicate that ERK5 signaling regulates glucose-induced ET-1 expression in diabetes. The ERK5/ET-1 pathway may provide a potential novel target for the treatment of diabetic angiopathy.
机译:内皮素1(ET-1)的上调引起血流改变和细胞外基质产生增加是糖尿病性血管病的特征。几种葡萄糖诱导的信号传导机制导致糖尿病性血管病中的ET-1上调。细胞外信号调节激酶5(ERK5)是MAPK家族的成员,在心血管发育中起关键作用。 ERK激酶(MEK)5是ERK5激活的特异性MEK。在这项研究中,我们检查了葡萄糖诱导的ERK5信号传导在糖尿病性血管病中介导ET-1表达中的作用。我们调查了1个月STZ诱导的糖尿病大鼠和人类大血管和微血管内皮细胞的视网膜,以研究ERK5依赖性ET-1的改变。葡萄糖(25 mmol / L)在内皮细胞处理24小时后引起ET-1 mRNA的显着上调以及ERK5和Kruppel样因子2(KLF2)的下调。同时,磷酸化-ERK5蛋白被还原。组成性活性MEK5(caMEK5)对ERK5的激活上调了KLF2并抑制了两种细胞系中ET-1的表达,而ERK5 siRNA转染导致ERK5和KLF2的减少以及ET-1 mRNA的表达增加。另外,caMEK5阻止了葡萄糖诱导的ET-1上调。此外,糖尿病的1个月引起视网膜ET-1 mRNA的显着增加和ERK5 mRNA表达的减少。这些数据表明ERK5信号调节糖尿病患者葡萄糖诱导的ET-1表达。 ERK5 / ET-1途径可能为糖尿病性血管病的治疗提供潜在的新靶标。

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