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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Oxidative stress-induced, poly(ADP-ribose) polymerase-dependent upregulation of ET-1 expression in chronic diabetic complications.
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Oxidative stress-induced, poly(ADP-ribose) polymerase-dependent upregulation of ET-1 expression in chronic diabetic complications.

机译：氧化应激诱导的慢性糖尿病并发症中ET-1表达的聚（ADP-核糖）聚合酶依赖性上调。

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Hyperglycemia in diabetes induces increased endothelin-1 (ET-1) production in the retina, kidney, and heart that may lead to hemodynamic impairment, permeability alteration, and increased extracellular matrix (ECM) protein production. Chronically elevated blood glucose levels may cause oxidative stress in these target tissues of diabetic complications. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme activated by DNA strand breaks due to oxidative stress. We investigated the role of PARP in regulating ET-1 expression and ET-1-induced abnormalities in the targets organs of diabetic complications. Male Sprague-Dawley rats were injected with streptozotocin to induce diabetes. Once diabetes was established, half of the diabetic rats were randomly chosen to receive PARP inhibitor 3-aminobenzamide for 4 months. In a second set of experiments, PARP-/- mice and their controls were fed for 2 months with either a normal rodent diet or a 30% galactose diet to induce a normoinsulinemic hyperhexosemic state. Tissues harvested at the conclusion of both experiments were then subjected to real-time RT-PCR analysis for mRNA expression and immunohistochemical assessment of oxidative stress. In both experiments, the hyperhexosemic state upregulated expression of ET-1 mRNA in the retina, kidney, and heart. Furthermore, upregulation of ET-1-dependent ECM transcripts, such as fibronectin and extradomain B-containing fibronectin, was noted in all tissues. These tissues also demonstrated oxidative stress, as evidenced by the presence of nuclei positive for 8-hydroxy-2'-deoxyguanosine. In contrast, inhibition of PARP, either through a chemical means in the diabetic rats or by genetic manipulation in the galactose-fed animals, prevented both oxidative stress and hyperhexosemia-induced upregulation of these genes. These results suggest that, in diabetes, oxidative stress and PARP activation may produce their effects through ET-1. Hence, blockade of such pathways may constitute potential adjuvant treatment modalities in chronicdiabetic complications.
机译：糖尿病中的高血糖症会导致视网膜，肾脏和心脏中内皮素1（ET-1）的产生增加，这可能导致血液动力学损害，通透性改变和细胞外基质（ECM）蛋白产生增加。长期升高的血糖水平可能会在这些糖尿病并发症的目标组织中引起氧化应激。聚（ADP-核糖）聚合酶（PARP）是一种由于氧化应激而被DNA链断裂激活的核酶。我们调查了PARP在糖尿病并发症靶器官中调节ET-1表达和ET-1诱导的异常的作用。给雄性Sprague-Dawley大鼠注射链脲佐菌素以诱发糖尿病。一旦建立了糖尿病，随机选择一半的糖尿病大鼠接受PARP抑制剂3-氨基苯甲酰胺4个月。在第二组实验中，以正常啮齿动物饮食或30％半乳糖饮食喂养PARP-/-小鼠及其对照组2个月，以诱导降血脂正常状态。然后将两个实验结束时收集的组织进行实时RT-PCR分析，以进行mRNA表达和氧化应激的免疫组化评估。在这两个实验中，高血氧状态上调了视网膜，肾脏和心脏中ET-1 mRNA的表达。此外，在所有组织中都注意到ET-1依赖性ECM转录本，例如纤连蛋白和含域外B的纤连蛋白的上调。这些组织还显示出氧化应激，如存在对8-羟基-2'-脱氧鸟苷呈阳性的核所证明。相反，通过糖尿病大鼠中的化学方法或通过半乳糖喂养的动物中的基因操作来抑制PARP，既可以防止氧化应激，又可以防止高血氧引起的这些基因的上调。这些结果表明，在糖尿病中，氧化应激和PARP激活可能通过ET-1产生作用。因此，在慢性糖尿病并发症中，此类途径的阻断可能构成潜在的辅助治疗方式。

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