Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes
Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes
复制标题
DOI：
10.1007/s00125-007-0734-9
复制
发表时间：
2007-09-01
期刊：
影响因子：
8.2
通讯作者：
Berkowitz, B. A.
中科院分区：
文献类型：
--
作者：
Zheng, L.;Du, Y.;Berkowitz, B. A.
目的/假设糖尿病导致视网膜中炎症反应的几种组分的产生上调，包括诱导型一氧化氮合酶（iNOS）。本研究的目的是研究iNOS在糖尿病视网膜病变的早期阶段的发病机制中的作用，使用iNOS缺陷型小鼠（iNos（-/-））。材料和方法iNos（-/-）小鼠和野生型（WT; C57 BL/6 J）小鼠糖尿病与链脲佐菌素或保持作为非糖尿病对照。在诱导糖尿病后的不同时间点处死小鼠，以评估血管组织病理学、神经节细胞层（GCL）中的细胞损失、视网膜厚度以及生化和生理异常。（ADP-核糖）（PAR）-修饰的蛋白质，内皮型一氧化氮合酶，前列腺素E-2，与非糖尿病WT小鼠相比，糖尿病2个月的WT小鼠视网膜中的超氧化物和白细胞停滞显著增加（p < 0.05）。在糖尿病iNos（-/-）小鼠中，除视网膜中PAR修饰的蛋白质外，所有这些异常均被抑制（p < 0.05）。与非糖尿病WT对照相比，在来自糖尿病9个月的WT小鼠的视网膜中，无细胞毛细血管和周细胞血影的数量显著增加，这些增加在糖尿病iNos（-/-）小鼠中被显著抑制（所有p < 0.05）。来自WT糖尿病小鼠的视网膜比来自其非糖尿病对照的视网膜显著更薄，而糖尿病iNos（-/-）小鼠免受这种异常的影响。我们在糖尿病WT或iNos（-/-）小鼠的GCL中没有发现细胞损失的证据。删除iNOS没有有益的影响糖尿病引起的异常electroretinografic.Conclusions/interpretation我们证明，炎症酶iNOS的发病机制中起着重要的作用，血管病变的特点，早期阶段的糖尿病视网膜病变小鼠。
Aims/hypothesis Diabetes results in the upregulation of the production of several components of the inflammatory response in the retina, including inducible nitric oxide synthase (iNOS). The aim of this study was to investigate the role of iNOS in the pathogenesis of the early stages of diabetic retinopathy using iNOS-deficient mice (iNos(-/-)).Materials and methods iNos(-/-) mice and wild-type (WT; C57BL/6J) mice were made diabetic with streptozotocin or kept as non-diabetic controls. Mice were killed at different time points after the induction of diabetes for assessment of vascular histopathology, cell loss in the ganglion cell layer (GCL), retinal thickness, and biochemical and physiological abnormalities.Results The concentrations of nitric oxide, nitration of proteins, poly(ADP-ribose) (PAR)-modified proteins, endothelial nitric oxide synthase, prostaglandin E-2, superoxide and leucostasis were significantly (p < 0.05) increased in retinas of WT mice diabetic for 2 months compared with non-diabetic WT mice. All of these abnormalities except PAR-modified proteins in retinas were inhibited (p < 0.05) in diabetic iNos (-/-) mice. The number of acellular capillaries and pericyte ghosts was significantly increased in retinas from WT mice diabetic for 9 months compared with non-diabetic WT controls, these increases being significantly inhibited in diabetic iNos (-/-) mice (p < 0.05 for all). Retinas from WT diabetic mice were significantly thinner than those from their non-diabetic controls, whereas diabetic iNos (-/-) mice were protected from this abnormality. We found no evidence of cell loss in the GCL of diabetic WT or iNos(-/-) mice. Deletion of iNos had no beneficial effect on diabetes-induced abnormalities on the electroretinogram.Conclusions/interpretation We demonstrate that the inflammatory enzyme iNOS plays an important role in the pathogenesis of vascular lesions characteristic of the early stages of diabetic retinopathy in mice.