The Transforming Growth Factor-β Pathway Is a Common Target of Drugs That Prevent Experimental Diabetic Retinopathy
The Transforming Growth Factor-β Pathway Is a Common Target of Drugs That Prevent Experimental Diabetic Retinopathy
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DOI：
10.2337/db08-1008
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发表时间：
2009-07-01
期刊：
影响因子：
7.7
通讯作者：
Lorenzi, Mara
中科院分区：
文献类型：
--
作者：
Gerhardinger, Chiara;Dagher, Zeina;Lorenzi, Mara
目的-预防糖尿病视网膜病变将受益于预防高血糖对视网膜血管影响的药物的可用性。我们旨在通过研究预防糖尿病大鼠视网膜毛细血管死亡的药物的分子效应来确定候选药物靶点。 研究设计和方法 - 我们检查了从链脲佐菌素诱导的糖尿病 6 个月的大鼠中分离的视网膜血管的基因表达谱，并将其与对照大鼠进行比较。然后，我们测试了具有不同作用机制的醛糖还原酶抑制剂索宾尼和阿司匹林是否可以预防糖尿病引起的常见分子异常。 Affymetrix GeneChip 大鼠基因组 230 2.0 阵列辅以实时 RT-PCR、免疫印迹和免疫组织化学。 结果——除了参与氧化应激、炎症、血管重塑和细胞凋亡的基因外，糖尿病大鼠的视网膜血管还显示出转化生长因子 (TGF)-β 途径的 20 个基因的差异表达。 TGF-β信号传导的完整环路，包括Smad2磷酸化，在视网膜血管中得到增强，但在神经视网膜中却没有增强。 Sorbinil 使 71% 与氧化应激相关的基因和 62% 与炎症相关的基因的表达正常化。阿司匹林对这两类的影响很小或没有影响。相反，这两种药物在减少 TGF-β 途径基因上调（索比尼为 55%，阿司匹林为 40%）和细胞凋亡（分别为 74% 和 42%）方面是一致的。 结论——氧化和炎症应激是多元醇途径在视网膜血管上留下的独特特征。然而，TGF-β 和细胞凋亡是预防糖尿病视网膜病变毛细血管死亡的最终目标。糖尿病 58:1659-1667, 2009
OBJECTIVE-Prevention of diabetic retinopathy would benefit from availability of drugs that preempt the effects of hyperglycemia on retinal vessels. We aimed to identify candidate drug targets by investigating the molecular effects of drugs that prevent retinal capillary demise in the diabetic rat.RESEARCH DESIGN AND METHODS-We examined the gene expression profile of retinal vessels isolated from rats with 6 months of streptozotocin-induced diabetes and compared it with that of control rats. We then tested whether the aldose reductase inhibitor sorbinil and aspirin, which have different mechanisms of action, prevented common molecular abnormalities induced by diabetes. The Affymetrix GeneChip Rat Genome 230 2.0 array was complemented by real-time RT-PCR, immunoblotting, and immunohistochemistry.RESULTS-The retinal vessels of diabetic rats showed differential expression of 20 genes of the transforming growth factor (TGF)-beta pathway, in addition to genes involved in oxidative stress, inflammation, vascular remodeling, and apoptosis. The complete loop of TGF-beta signaling, including Smad2 phosphorylation, was enhanced in the retinal vessels, but not in the neural retina. Sorbinil normalized the expression of 71% of the genes related to oxidative stress and 62% of those related to inflammation. Aspirin had minimal or no effect on these two categories. The two drugs were instead concordant in reducing the upregulation of genes of the TGF-beta pathway (55% for sorbinil and 40% for aspirin) and apoptosis (74 and 42%, respectively).CONCLUSIONS-Oxidative and inflammatory stress is the distinct signature that the polyol pathway leaves on retinal vessels. TGF-beta and apoptosis are, however, the ultimate targets to prevent the capillary demise in diabetic retinopathy. Diabetes 58:1659-1667, 2009