Whole genome assessment of the retinal response to diabetes reveals a progressive neurovascular inflammatory response
Whole genome assessment of the retinal response to diabetes reveals a progressive neurovascular inflammatory response
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DOI：
10.1186/1755-8794-1-26
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发表时间：
2008-06-13
影响因子：
2.7
通讯作者：
Freeman, Willard M.
中科院分区：
文献类型：
--
作者：
Brucklacher, Robert M.;Patel, Kruti M.;Freeman, Willard M.
背景：尽管对糖尿病视网膜病变的认识有所进展，但对糖尿病视网膜分子变化的性质和时间过程的描述还不完全。结果：采用链脲佐菌素诱导的糖尿病大鼠模型，观察糖尿病1个月和3个月后视网膜通透性、caspase活性和基因表达的变化。通过全基因组微阵列鉴定基因表达变化，并通过qPCR在与微阵列分析中使用的相同动物集合中确认，随后在独立的动物集合中验证。血管通透性和半胱氨酸天冬氨酸氨基转移酶-3活性在糖尿病3个月时升高，而不是1个月。糖尿病3个月后的基因表达变化明显多于1个月后。对选定的与炎症、微血管和神经功能相关的基因进行定量PCR验证，证实了多组独立动物中基因表达的变化。结论：这些通透性、细胞凋亡和基因表达的变化为随着糖尿病病程的增加而进行性视网膜功能障碍提供了进一步的证据。在多组动物中证实的特定基因表达的变化表明，促炎、抗血管屏障和神经退行性变化伴随着细胞凋亡和血管通透性的功能性增加。这些反应与临床记录的糖尿病视网膜病变的炎症反应是相同的，这表明该模型可用于测试抗炎疗法。
Background: Despite advances in the understanding of diabetic retinopathy, the nature and time course of molecular changes in the retina with diabetes are incompletely described. This study characterized the functional and molecular phenotype of the retina with increasing durations of diabetes.Results: Using the streptozotocin-induced rat model of diabetes, levels of retinal permeability, caspase activity, and gene expression were examined after 1 and 3 months of diabetes. Gene expression changes were identified by whole genome microarray and confirmed by qPCR in the same set of animals as used in the microarray analyses and subsequently validated in independent sets of animals. Increased levels of vascular permeability and caspase-3 activity were observed at 3 months of diabetes, but not 1 month. Significantly more and larger magnitude gene expression changes were observed after 3 months than after 1 month of diabetes. Quantitative PCR validation of selected genes related to inflammation, microvasculature and neuronal function confirmed gene expression changes in multiple independent sets of animals.Conclusion: These changes in permeability, apoptosis, and gene expression provide further evidence of progressive retinal malfunction with increasing duration of diabetes. The specific gene expression changes confirmed in multiple sets of animals indicate that pro-inflammatory, anti-vascular barrier, and neurodegenerative changes occur in tandem with functional increases in apoptosis and vascular permeability. These responses are shared with the clinically documented inflammatory response in diabetic retinopathy suggesting that this model may be used to test anti-inflammatory therapeutics.