Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912.
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912.
Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):13248-13253. doi: 10.1073/pnas.1718592114. Epub 2017 Nov 27.
The potential therapeutic effects of agonistic analogs of growth hormone-releasing hormone (GHRH) and their mechanism of action were investigated in diabetic retinopathy (DR). Streptozotocin-induced diabetic rats (STZ-rats) were treated with 15 μg/kg GHRH agonist, MR-409, or GHRH antagonist, MIA-602. At the end of treatment, morphological and biochemical analyses assessed the effects of these compounds on retinal neurovascular injury induced by hyperglycemia. The expression levels of GHRH and its receptor (GHRH-R) measured by qPCR and Western blotting were significantly down-regulated in retinas of STZ-rats and in human diabetic retinas (postmortem) compared with their respective controls. Treatment of STZ-rats with the GHRH agonist, MR-409, prevented retinal morphological alteration induced by hyperglycemia, particularly preserving survival of retinal ganglion cells. The reverse, using the GHRH antagonist, MIA-602, resulted in worsening of retinal morphology and a significant alteration of the outer retinal layer. Explaining these results, we have found that MR-409 exerted antioxidant and anti-inflammatory effects in retinas of the treated rats, as shown by up-regulation of NRF-2-dependent gene expression and down-regulation of proinflammatory cytokines and adhesion molecules. MR-409 also significantly down-regulated the expression of vascular endothelial growth factor while increasing that of pigment epithelium-derived factor in diabetic retinas. These effects correlated with decreased vascular permeability. In summary, our findings suggest a neurovascular protective effect of GHRH analogs during the early stage of diabetic retinopathy through their antioxidant and anti-inflammatory properties.
生长激素释放激素（GHRH）激动剂及其作用机制在糖尿病视网膜病变（DR）中的潜在治疗作用进行了研究。用 15μg/kg GHRH 激动剂 MR-409 或 GHRH 拮抗剂 MIA-602 治疗链脲佐菌素诱导的糖尿病大鼠（STZ-大鼠）。在治疗结束时，形态和生化分析评估了这些化合物对高血糖诱导的视网膜神经血管损伤的影响。与各自的对照相比，qPCR 和 Western blot 测量的 GHRH 和其受体（GHRH-R）的表达水平在 STZ-大鼠和人糖尿病视网膜（尸检）中显着下调。用 GHRH 激动剂 MR-409 治疗 STZ-大鼠可预防高血糖引起的视网膜形态改变，特别是可维持视网膜神经节细胞的存活。使用 GHRH 拮抗剂 MIA-602 则相反，导致视网膜形态恶化和外视网膜层的显着改变。解释这些结果，我们发现 MR-409 在治疗大鼠的视网膜中发挥抗氧化和抗炎作用，如 NRF-2 依赖性基因表达上调和促炎细胞因子和粘附分子下调所示。MR-409 还显着下调了血管内皮生长因子的表达，同时增加了糖尿病视网膜中色素上皮衍生因子的表达。这些作用与血管通透性降低有关。总之，我们的研究结果表明，GHRH 类似物通过其抗氧化和抗炎特性在糖尿病视网膜病变的早期阶段具有神经血管保护作用。
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