IGFBP-3 and TNF-α Regulate Retinal Endothelial Cell Apoptosis
IGFBP-3 and TNF-α Regulate Retinal Endothelial Cell Apoptosis
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DOI：
10.1167/iovs.13-12497
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发表时间：
2013-08-01
影响因子：
4.4
通讯作者：
Steinle, Jena J.
中科院分区：
文献类型：
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作者：
Zhang, Qiuhua;Jiang, Youde;Steinle, Jena J.
目的.我们假设胰岛素样生长因子结合蛋白3（IGFBP-3）信号的缺失会导致类似于早期糖尿病的视网膜神经元改变。为了更好地理解IGFBP-3在视网膜中的作用，与野生型同窝仔相比，评估IGFBP-3敲除（KO）小鼠的神经元、血管和功能变化。我们还在血糖正常或高血糖下培养视网膜内皮细胞（REC），以确定IGFBP-3和TNF-α之间的相互作用，因为数据表明这两种蛋白质均受β-肾上腺素能受体调节，并产生拮抗反应。我们还用化合物49 b处理了一些细胞，化合物49 b是我们先前报道的调节IGFBP-3和TNF-α-受体的新型β-肾上腺素能受体激动剂。视网膜电图分析显示IGFBP-3基因敲除小鼠的B波和振荡电位振幅降低，对应于细胞凋亡增加。在IGFBP-3 KO小鼠中，视网膜厚度和神经节细胞层中的细胞数量减少。正如预期的那样，IGFBP-3的缺失与TNF-α水平的升高相关。当TNF-α和IGFBP-3应用于REC时，它们拮抗作用，IGFBP-3抑制细胞凋亡，TNF-α促进细胞凋亡。由于它们的拮抗性质，结果表明REC的凋亡可能取决于哪种蛋白（IGFBP-3与TNF-α）是活性的。总之，IGFBP-3信号传导的丧失导致与早期阶段糖尿病视网膜病变中观察到的神经元变化相似的表型，包括TNF-α水平升高。
PURPOSE. We hypothesized that loss of insulin-like growth factor binding protein 3 (IGFBP-3) signaling would produce neuronal changes in the retina similar to early diabetes.METHODS. To understand better the role of IGFBP-3 in the retina, IGFBP-3 knockout (KO) mice were evaluated for neuronal, vascular, and functional changes compared to wild-type littermates. We also cultured retinal endothelial cells (REC) in normoglycemia or hyperglycemia to determine the interaction between IGFBP-3 and TNF-alpha, as data indicate that both proteins are regulated by beta-adrenergic receptors and respond antagonistically. We also treated some cells with Compound 49b, a novel beta-adrenergic receptor agonist we have reported previously to regulate IGFBP-3 and TNF-alpha.RESULTS. Electroretinogram analyses showed decreased B-wave and oscillatory potential amplitudes in the IGFBP-3 KO mice, corresponding to increased apoptosis. Retinal thickness and cell numbers in the ganglion cell layer were reduced in the IGFBP-3 KO mice. As expected, loss of IGFBP-3 was associated with increased TNF-alpha levels. When TNF-alpha and IGFBP-3 were applied to REC, they worked antagonistically, with IGFBP-3 inhibiting apoptosis and TNF-alpha promoting apoptosis. Due to their antagonistic nature, results suggest that apoptosis of REC may depend upon which protein (IGFBP-3 versus TNF-alpha) is active.CONCLUSIONS. Taken together, loss of IGFBP-3 signaling results in a phenotype similar to neuronal changes observed in diabetic retinopathy in the early phases, including increased TNF-alpha levels.