Rossi S, Maisto R, Gesualdo C, Trotta M C, Ferraraccio F, Kaneva M K, Getting S J, Surace E, Testa F, Simonelli F, Grieco P, Merlino F, Perretti M, D'Amico M, Di Filippo C
Multidisciplinary Department of Medical-Surgical and Dental Specialties, Second University of Naples, 80138 Naples, Italy.
Department of Experimental Medicine, Second University of Naples, 80138 Naples, Italy.
Mediators Inflamm. 2016;2016:7368389. doi: 10.1155/2016/7368389. Epub 2016 Jan 12.
We hypothesize that melanocortin receptors (MC) could activate tissue protective circuit in a model of streptozotocin- (STZ-) induced diabetic retinopathy (DR) in mice. At 12-16 weeks after diabetes induction, fluorescein angiography (FAG) revealed an approximate incidence of 80% microvascular changes, typical of DR, in the animals, without signs of vascular leakage. Occludin progressively decreased in the retina of mice developing retinopathy. qPCR of murine retina revealed expression of two MC receptors, Mc1r and Mc5r. The intravitreal injection (5 μL) of the selective MC1 small molecule agonist BMS-470539 (33 μmol) and the MC5 peptidomimetic agonist PG-901 (7.32 nM) elicited significant protection with regular course and caliber of retinal vessels, as quantified at weeks 12 and 16 after diabetes induction. Mouse retina homogenate settings indicated an augmented release of IL-1α, IL-1β, IL-6, MIP-1α, MIP-2α, MIP-3α, and VEGF from diabetic compared to nondiabetic mice. Application of PG20N or AGRP and MC5 and MC1 antagonist, respectively, augmented the release of cytokines, while the agonists BMS-470539 and PG-901 almost restored normal pattern of these mediators back to nondiabetic values. Similar changes were quantified with respect to Ki-67 staining. Finally, application of MC3-MC4 agonist/antagonists resulted to be inactive with respect to all parameters under assessment.
我们假设黑素皮质素受体（MC）可在链脲佐菌素（STZ）诱导的小鼠糖尿病视网膜病变（DR）模型中激活组织保护回路。在诱导糖尿病后的12 - 16周，荧光素血管造影（FAG）显示，动物中约80%出现微血管变化，这是DR的典型表现，且无血管渗漏迹象。在发生视网膜病变的小鼠视网膜中，闭合蛋白逐渐减少。对小鼠视网膜进行qPCR检测发现了两种MC受体，即Mc1r和Mc5r的表达。玻璃体内注射（5 μL）选择性MC1小分子激动剂BMS - 470539（33 μmol）和MC5拟肽激动剂PG - 901（7.32 nM），在诱导糖尿病后的第12周和第16周进行量化评估时，可使视网膜血管的走行和管径保持正常，从而产生显著的保护作用。小鼠视网膜匀浆检测结果表明，与非糖尿病小鼠相比，糖尿病小鼠的IL - 1α、IL - 1β、IL - 6、MIP - 1α、MIP - 2α、MIP - 3α和VEGF释放增加。分别应用PG20N或AGRP以及MC5和MC1拮抗剂可增加细胞因子的释放，而激动剂BMS - 470539和PG - 901几乎可使这些介质的释放模式恢复到非糖尿病小鼠的正常水平。关于Ki - 67染色也进行了类似的量化分析。最后，应用MC3 - MC4激动剂/拮抗剂对所有评估参数均无活性。
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