Nuclear factor of activated T cells is activated in the endothelium of retinal microvessels in diabetic mice.
Nuclear factor of activated T cells is activated in the endothelium of retinal microvessels in diabetic mice.
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DOI：
10.1155/2015/428473
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发表时间：
2015
影响因子：
4.3
通讯作者：
Gomez MF
中科院分区：
文献类型：
--
作者：
Zetterqvist AV;Blanco F;Öhman J;Kotova O;Berglund LM;de Frutos Garcia S;Al-Naemi R;Wigren M;McGuire PG;Gonzalez Bosc LV;Gomez MF
糖尿病视网膜病变（DR）的发病机制尚不清楚，但高血糖是一个既定的危险因素。已证明内皮功能障碍和Ca 2+信号传导的变化先于DR的发生。我们最近证明，高细胞外葡萄糖激活脑动脉和主动脉中的Ca 2 +/钙调神经磷酸酶依赖性转录因子NFAT，促进炎症标志物的表达。在这里，我们表明，使用共聚焦免疫荧光，NFAT是在视网膜微血管内皮细胞的表达，并很容易被高葡萄糖激活。这被NFAT阻断剂A-285222以及外核苷酸酶腺苷三磷酸双磷酸酶抑制，表明涉及细胞外核苷酸释放的机制。由IP-GTT（腹膜内葡萄糖耐量试验）诱导的急性高血糖导致NFAT荧光素酶报告小鼠视网膜血管中NFATc 3核积累和NFAT依赖性转录活性增加。在秋田（Ins 2 +/−）和链脲佐菌素-（STZ-）诱导的糖尿病小鼠中，视网膜血管中的NFAT转录活性升高。用A-285222体内抑制NFAT可降低视网膜血管中OPN和ICAM-1 mRNA的表达，防止糖尿病驱动的视网膜中抗炎性IL-10下调，并消除糖尿病小鼠中观察到的血管通透性增加。结果确定NFAT信号传导作为治疗糖尿病微血管并发症的假定靶点。
The pathogenesis of diabetic retinopathy (DR) remains unclear but hyperglycemia is an established risk factor. Endothelial dysfunction and changes in Ca2+ signaling have been shown to precede the onset of DR. We recently demonstrated that high extracellular glucose activates the Ca2+/calcineurin-dependent transcription factor NFAT in cerebral arteries and aorta, promoting the expression of inflammatory markers. Here we show, using confocal immunofluorescence, that NFAT is expressed in the endothelium of retinal microvessels and is readily activated by high glucose. This was inhibited by the NFAT blocker A-285222 as well as by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. Acute hyperglycemia induced by an IP-GTT (intraperitoneal glucose tolerance test) resulted in increased NFATc3 nuclear accumulation and NFAT-dependent transcriptional activity in retinal vessels of NFAT-luciferase reporter mice. In both Akita (Ins2+/−) and streptozotocin- (STZ-) induced diabetic mice, NFAT transcriptional activity was elevated in retinal vessels. In vivo inhibition of NFAT with A-285222 decreased the expression of OPN and ICAM-1 mRNA in retinal vessels, prevented a diabetes driven downregulation of anti-inflammatory IL-10 in retina, and abrogated the increased vascular permeability observed in diabetic mice. Results identify NFAT signaling as a putative target for treatment of microvascular complications in diabetes.
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影响因子：
2.1
作者：
Kase, Satoru;Yokoi, Masahiko;Uede, Toshimitsu
通讯作者：
Uede, Toshimitsu
影响因子：
--
作者：
Kern, Timothy S.
通讯作者：
Kern, Timothy S.
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
7.7
作者：
Kwan, EP;Xie, L;Gaisano, HY
通讯作者：
Gaisano, HY
影响因子：
4.3
作者：
Lai AK;Lo AC
通讯作者：
Lo AC