Simão Sónia, Santos Daniela F, Silva Gabriela A
Centre for Biomedical Research (CBMR), University of Algarve, Campus Gambelas, 8005-139, Faro, Portugal.
CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056, Lisbon, Portugal.
Angiogenesis. 2017 Feb;20(1):175-181. doi: 10.1007/s10456-016-9526-5. Epub 2016 Oct 1.
There is growing evidence on the role of ocular renin-angiotensin system (RAS) in the development of diabetic retinopathy (DR), particularly due to the trigger of oxidative stress and angiogenesis. Despite this there is no effective RAS-based therapy in DR capable of preventing retinal damage induced by RAS activation. We recently described that retinal pigment epithelium (RPE) cells express the main components of the RAS. We here propose to investigate the role of glucose upon the retinal RAS and whether aliskiren, a direct renin inhibitor, protects RPE cells from angiogenesis and oxidative stress. RPE cells were chosen as target since one of the first events in DR is the dysfunction of the RPE retinal layer, which as a key function in maintaining the integrity of the retina. We found that the RAS present in the RPE cells was deregulated by hyperglycemic glucose concentrations. Exposure of RPE cells to angiotensin II increased the levels of the main pro-angiogenic factor, vascular endothelial growth factor (VEGF) in a concentration-dependent manner. Additionally, angiotensin II also stimulated the production of reactive oxygen species in RPE cells. Treatment of RPE cells with aliskiren decreased the levels of oxidative stress and promoted the expression of anti-angiogenic factors such as the pigment epithelium-derived factor and the VEGFb isoform. Our findings demonstrate that the RAS is deregulated in hyperglycemic conditions and that aliskiren successfully protected RPE cells from RAS over activation. These anti-angiogenic and antioxidant properties described for aliskiren over RPE cells suggest that this drug has potential to be used in the treatment of diabetic retinopathy.
越来越多的证据表明，眼部肾素-血管紧张素系统（RAS）在糖尿病视网膜病变（DR）的发生发展中发挥作用，尤其是由于氧化应激和血管生成的触发。尽管如此，在DR中尚无有效的基于RAS的疗法能够预防由RAS激活引起的视网膜损伤。我们最近描述了视网膜色素上皮（RPE）细胞表达RAS的主要成分。我们在此提议研究葡萄糖对视网膜RAS的作用，以及直接肾素抑制剂阿利吉仑是否能保护RPE细胞免受血管生成和氧化应激的影响。选择RPE细胞作为研究对象是因为DR最早出现的事件之一是RPE视网膜层功能障碍，而RPE视网膜层在维持视网膜完整性方面起关键作用。我们发现，高血糖浓度会使RPE细胞中的RAS失调。将RPE细胞暴露于血管紧张素II会以浓度依赖的方式增加主要促血管生成因子血管内皮生长因子（VEGF）的水平。此外，血管紧张素II还会刺激RPE细胞中活性氧的产生。用阿利吉仑处理RPE细胞可降低氧化应激水平，并促进抗血管生成因子如色素上皮衍生因子和VEGFb亚型的表达。我们的研究结果表明，在高血糖条件下RAS失调，并且阿利吉仑成功地保护RPE细胞免受RAS过度激活的影响。阿利吉仑对RPE细胞所具有的这些抗血管生成和抗氧化特性表明，这种药物有潜力用于治疗糖尿病视网膜病变。
