Adrenergic and serotonin receptors affect retinal superoxide generation in diabetic mice: relationship to capillary degeneration and permeability
Adrenergic and serotonin receptors affect retinal superoxide generation in diabetic mice: relationship to capillary degeneration and permeability
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DOI：
10.1096/fj.14-269431
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发表时间：
2015-05-01
期刊：
影响因子：
4.8
通讯作者：
Kern，Timothy S.
中科院分区：
文献类型：
--
作者：
Du，Yunpeng;Cramer，Megan;Kern，Timothy S.
活性氧在糖尿病视网膜病变的发病机制中起重要作用。我们研究了肾上腺素能受体和5 -羟色胺受体在高糖视网膜和661W视网膜细胞产生超氧化物中的作用，以及α1-肾上腺素能受体（AR）在实验性糖尿病C57Bl/6J小鼠（和对照组）视网膜病变血管病变2和8个月后的作用。与5 mM葡萄糖相比，30 mM葡萄糖培养细胞或视网膜外植体诱导超氧化物生成。通过药理抑制α - 1- ar（一种gq偶联受体）或gs偶联血清素（5-HT2、5-HT4、5-HT6和5-HT7）受体或激活gi偶联α - 2- ar，可以降低或消除这种反应。在葡萄糖升高时，α1-AR通过磷脂酶C、肌醇三磷酸诱导的Ca2+释放和NADPH氧化酶产生超氧化物，药物抑制这些反应可防止超氧化物的增加。糖尿病患者视网膜超氧化物的生成、促炎蛋白的表达和视网膜毛细血管变性均被每日多沙唑嗪或夹竹桃碱（α - 1- ar和NADPH氧化酶抑制剂）显著抑制，但血管通透性的增加未受显著影响。肾上腺素能受体，也许还有其他gpcr，代表了抑制糖尿病视网膜病变重要特征发展的新靶点。-Du， Y., Cramer， M., Lee， C. A., Tang， J., Muthusamy， A., Antonetti， D. A., Jin， H., Palczewski， K., Kern， T. S.肾上腺素能和血清素受体影响糖尿病小鼠视网膜超氧化物生成：与毛细血管变性和通透性的关系。
Reactive oxygen species play an important role in the pathogenesis of diabetic retinopathy. We studied the role of adrenergic and serotonin receptors in the generation of superoxide by retina and 661W retinal cells in high glucose and of the α1-adrenergic receptor (AR) on vascular lesions of the retinopathy in experimentally diabetic C57Bl/6J mice (and controls) after 2 and 8 months. Compared with 5 mM glucose, incubating cells or retinal explants in 30 mM glucose induced superoxide generation. This response was reduced or ablated by pharmacologic inhibition of the α1-AR (a Gq-coupled receptor) or Gs-coupled serotonin (5-HT2, 5-HT4, 5-HT6, and 5-HT7) receptors or by activation of the Gi-coupled α2-AR. In elevated glucose, the α1-AR produced superoxide via phospholipase C, inositol triphosphate-induced Ca2+ release, and NADPH oxidase, and pharmacologic inhibition of these reactions prevented the superoxide increase. Generation of retinal superoxide, expression of proinflammatory proteins, and degeneration of retinal capillaries in diabetes all were significantly inhibited with daily doxazosin or apocynin (inhibitors of α1-AR and NADPH oxidase, respectively), but increased vascular permeability was not significantly affected. Adrenergic receptors, and perhaps other GPCRs, represent novel targets for inhibiting the development of important features of diabetic retinopathy.—Du, Y., Cramer, M., Lee, C. A., Tang, J., Muthusamy, A., Antonetti, D. A., Jin, H., Palczewski, K., Kern, T. S. Adrenergic and serotonin receptors affect retinal superoxide generation in diabetic mice: relationship to capillary degeneration and permeability.