miR-146a-Mediated extracellular matrix protein production in chronic diabetes complications.
miR-146a-Mediated extracellular matrix protein production in chronic diabetes complications.
复制标题
DOI：
10.2337/db11-0478
复制
发表时间：
2011-11
期刊：
影响因子：
7.7
通讯作者：
Chakrabarti S
中科院分区：
文献类型：
--
作者：
Feng B;Chen S;McArthur K;Wu Y;Sen S;Ding Q;Feldman RD;Chakrabarti S
MicroRNAs(MiRNAs)通过转录调控，调节几个细胞过程。在糖尿病中，细胞外基质蛋白纤维连接蛋白(FN)的产生增加是已知的通过组蛋白乙酰化p300发生的。在这里，我们研究了miR-146a，一种针对Fn的miRNA，在糖尿病患者Fn产生中的作用及其与p300的关系。检测不同葡萄糖水平下大血管和视网膜微血管内皮细胞MIR-146a的表达。检测有或无miR-146a模拟或Anagomir转染组FN信使RNA的表达和蛋白水平。用荧光素酶分析法检测miR-146a与FN3‘-非翻译区的结合。同样，对1型糖尿病大鼠的视网膜进行了玻璃体内注射或不注射miR-146a模拟物的研究。用原位杂交技术对视网膜miR-146a进行定位。分析了1型和2型糖尿病动物的心脏和肾脏组织。与5 mmoL/L葡萄糖相比，25 mmoL/L葡萄糖降低了两种细胞miR-146a的表达，增加了Fn的表达。MiR-146a模拟转染组可阻止这种改变，而在5 mmol/L葡萄糖溶液中，miR-146a反式转染组细胞内Fn表达上调。荧光素酶检测证实miR-146a与Fn 3‘-UTR结合。MIR-146a定位于视网膜内皮细胞，糖尿病时MIR-146a表达降低。玻璃体内模拟注射miR-146a可恢复糖尿病大鼠视网膜miR-146a，降低Fn。进一步的实验表明，p300调控miR-146a。在1型和2型糖尿病动物的视网膜、肾脏和心脏中也发现了类似的变化。这些研究显示了一种新的、葡萄糖诱导的分子机制，其中miR-146a参与了调节糖尿病细胞外基质蛋白产生的转录电路。
microRNAs (miRNAs), through transcriptional regulation, modulate several cellular processes. In diabetes, increased extracellular matrix protein fibronectin (FN) production is known to occur through histone acetylator p300. Here, we investigated the role of miR-146a, an FN-targeting miRNA, on FN production in diabetes and its relationship with p300. miR-146a expressions were measured in endothelial cells from large vessels and retinal microvessels in various glucose levels. FN messenger RNA expression and protein levels with or without miR-146a mimic or antagomir transfection were examined. A luciferase assay was performed to detect miR-146a’s binding to FN 3′–untranslated region (UTR). Likewise, retinas from type 1 diabetic rats were studied with or without an intravitreal injection of miR-146a mimic. In situ hybridization was used to localize retinal miR-146a. Cardiac and renal tissues were analyzed from type 1 and type 2 diabetic animals. A total of 25 mmol/L glucose decreased miR-146a expression and increased FN expression compared with 5 mmol/L glucose in both cell types. miR-146a mimic transfection prevented such change, whereas miR-146a antagomir transfection in the cells in 5 mmol/L glucose caused FN upregulation. A luciferase assay confirmed miR-146a’s binding to FN 3′-UTR. miR-146a was localized in the retinal endothelial cells and was decreased in diabetes. Intravitreal miR-146a mimic injection restored retinal miR-146a and decreased FN in diabetes. Additional experiments showed that p300 regulates miR-146a. Similar changes were seen in the retinas, kidneys, and hearts in type 1 and type 2 diabetic animals. These studies showed a novel, glucose-induced molecular mechanism in which miR-146a participates in the transcriptional circuitry regulating extracellular matrix protein production in diabetes.
登录
查看更多内容
影响因子：
--
作者：
Kern, Timothy S.
通讯作者：
Kern, Timothy S.
影响因子：
9.8
作者：
Astrof S;Hynes RO
通讯作者：
Hynes RO
影响因子：
4.4
作者：
Kuiper, Esther J.;Hughes, John M.;Klaassen, Ingeborg
通讯作者：
Klaassen, Ingeborg
影响因子：
3.5
作者：
Chen, Ting;Li, Zhoubin;Zhu, Jianhua
通讯作者：
Zhu, Jianhua
影响因子：
8
作者：
Chen, Shali;Khan, Zia A.;Chakrabarti, Subrata
通讯作者：
Chakrabarti, Subrata