Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA.
Diabetologia. 2011 Jun;54(6):1567-78. doi: 10.1007/s00125-011-2061-4. Epub 2011 Mar 4.
AIMS/HYPOTHESIS: Recent studies have demonstrated that cannabinoid-1 (CB(1)) receptor blockade ameliorated inflammation, endothelial and/or cardiac dysfunction, and cell death in models of nephropathy, atherosclerosis and cardiomyopathy. However the role of CB(1) receptor signalling in diabetic retinopathy remains unexplored. Using genetic deletion or pharmacological inhibition of the CB(1) receptor with SR141716 (rimonabant) in a rodent model of diabetic retinopathy or in human primary retinal endothelial cells (HREC) exposed to high glucose, we explored the role of CB(1) receptors in the pathogenesis of diabetic retinopathy.
Diabetes was induced using streptozotocin in C57BL/6J Cb(1) (also known as Cnr1)(+/+) and Cb(1)(-/-) mice aged 8 to 12 weeks. Samples from mice retina or HREC were used to determine: (1) apoptosis; (2) activity of nuclear factor kappa B, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), poly (ADP-ribose) polymerase and caspase-3; (3) content of 3-nitrotyrosine and reactive oxygen species; and (4) activation of p38/Jun N-terminal kinase/mitogen-activated protein kinase (MAPK).
Deletion of CB(1) receptor or treatment of diabetic mice with CB(1) receptor antagonist SR141716 prevented retinal cell death. Treatment of diabetic mice or HREC cells exposed to high glucose with SR141716 attenuated the oxidative and nitrative stress, and reduced levels of nuclear factor κB, ICAM-1 and VCAM-1. In addition, SR141716 attenuated the diabetes- or high glucose-induced pro-apoptotic activation of MAPK and retinal vascular cell death.
CONCLUSIONS/INTERPRETATION: Activation of CB(1) receptors may play an important role in the pathogenesis of diabetic retinopathy by facilitating MAPK activation, oxidative stress and inflammatory signalling. Conversely, CB(1) receptor inhibition may be beneficial in the treatment of this devastating complication of diabetes.
目的/假设：最近的研究表明，大麻素-1（CB（1））受体阻断剂可改善肾病、动脉粥样硬化和心肌病模型中的炎症、内皮和/或心脏功能障碍以及细胞死亡。然而，CB（1）受体信号在糖尿病性视网膜病变中的作用仍未得到探索。在糖尿病性视网膜病变的啮齿动物模型中或在暴露于高葡萄糖的人原代视网膜内皮细胞（HREC）中，使用 CB（1）受体的遗传缺失或药理学抑制（用 SR141716[利莫那班]），我们探讨了 CB（1）受体在糖尿病性视网膜病变发病机制中的作用。
使用链脲佐菌素在 8 至 12 周龄的 C57BL/6J Cb（1）（也称为 Cnr1）（+/+）和 Cb（1）（-/-）小鼠中诱导糖尿病。使用来自小鼠视网膜或 HREC 的样本来确定：（1）细胞凋亡；（2）核因子 kappa B、细胞间黏附分子 1（ICAM-1）、血管细胞黏附分子 1（VCAM-1）、多聚（ADP-核糖）聚合酶和半胱天冬酶-3的活性；（3）3-硝基酪氨酸和活性氧的含量；和（4）p38/Jun N-末端激酶/丝裂原激活蛋白激酶（MAPK）的激活。
CB（1）受体的缺失或用 CB（1）受体拮抗剂 SR141716 治疗糖尿病小鼠可防止视网膜细胞死亡。用 SR141716 治疗糖尿病小鼠或暴露于高葡萄糖的 HREC 细胞可减轻氧化和硝化应激，并降低核因子 κB、ICAM-1 和 VCAM-1 的水平。此外，SR141716 可减轻糖尿病或高葡萄糖诱导的 MAPK 促凋亡激活和视网膜血管细胞死亡。
结论/解释：CB（1）受体的激活可能通过促进 MAPK 激活、氧化应激和炎症信号传导在糖尿病性视网膜病变的发病机制中起重要作用。相反，CB（1）受体抑制可能有益于这种糖尿病毁灭性并发症的治疗。
