Intravitreal injection of IGFBP-3 restores normal insulin signaling in diabetic rat retina.
Intravitreal injection of IGFBP-3 restores normal insulin signaling in diabetic rat retina.
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DOI：
10.1371/journal.pone.0093788
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Steinle JJ
中科院分区：
文献类型：
--
作者：
Jiang Y;Zhang Q;Steinle JJ
糖尿病诱导的生长因子结合蛋白3（IGFBP-3）和肿瘤坏死因子α（TNFα）的变化与糖尿病视网膜病变中胰岛素受体信号转导减少有关。我们先前在糖尿病大鼠视网膜中的研究表明，化合物49 b，一种新型β-肾上腺素能受体激动剂，通过增加IGFBP-3和降低TNFα来预防糖尿病变化，从而恢复胰岛素信号传导并保护免受糖尿病视网膜病变。本研究旨在确定单独IGFBP-3 NB（IGFBP-3的非IGF-1结合形式）的增强表达是否足以模拟化合物49 b在预防糖尿病视网膜病变中的全部作用，以及测试IGFBP-3 NB是否与正常胰岛素信号转导的恢复有关。在开始链脲佐菌素诱导的糖尿病后两个月，大鼠右眼接受单次玻璃体内注射IGFBP-3 NB质粒。注射后4天，处死前进行视网膜电图（ERG）分析。使用Western印迹或ELISA分析来自对照、糖尿病、糖尿病+对照质粒和糖尿病+ IGFBP-3 NB的全视网膜裂解物的IGFBP-3、TNFα、细胞因子信号传导抑制因子3（SOCS 3）和胰岛素受体信号传导伴侣。数据显示，在糖尿病动物中单次眼内注射IGFBP-3 NB可显著降低TNFα水平，同时IRS-1 Ser 307、SOCS 3和促凋亡标志物减少，同时恢复胰岛素受体磷酸化并增加抗凋亡标志物水平。这些细胞变化与视网膜功能的恢复有关。我们的研究结果证实IGFBP-3是胰岛素受体/TNFα通路的关键调节因子，也是糖尿病视网膜病变的潜在治疗靶点。
Diabetes-induced changes in growth factor binding protein 3 (IGFBP-3) and tumor necrosis factor alpha (TNFα) have been linked to decreased insulin receptor signaling in diabetic retinopathy. Our previous studies in retinas of diabetic rats have shown that Compound 49b, a novel β-adrenergic receptor agonist, prevented diabetic changes by increasing IGFBP-3 and decreasing TNFα, thus restoring insulin signaling and protection against diabetic retinopathy. The current study was designed to determine whether boosted expression of IGFBP-3 NB (a non-IGF-1 binding form of IGFBP-3) alone is sufficient to mimic the full actions of Compound 49b in protecting against diabetic retinopathy, as well as testing whether IGFBP-3 NB is linked to a restoration of normal insulin signal transduction. Two months after initiation of streptozotocin-induced diabetes, rats received a single intravitreal injection of IGFBP-3 NB plasmid in the right eye. Four days after injection, electroretinogram (ERG) analyses were performed prior to sacrifice. Whole retinal lysates from control, diabetic, diabetic + control plasmid, and diabetic+ IGFBP-3 NB were analyzed for IGFBP-3, TNFα, suppressor of cytokine signaling 3 (SOCS3), and insulin receptor signaling partners using Western blotting or ELISA. Data show that a single intraocular injection of IGFBP-3 NB in diabetic animals significantly reduced TNFα levels, concomitant with reductions in IRS-1Ser307, SOCS3, and pro-apoptotic markers, while restoring insulin receptor phosphorylation and increasing anti-apoptotic marker levels. These cellular changes were linked to restoration of retinal function. Our findings establish IGFBP-3 as a pivotal regulator of the insulin receptor/TNFα pathway and a potential therapeutic target for diabetic retinopathy.
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影响因子：
4.8
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