Role of nonproteolytically activated prorenin in pathologic, but not physiologic, retinal neovascularization
Role of nonproteolytically activated prorenin in pathologic, but not physiologic, retinal neovascularization
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DOI：
10.1167/iovs.06-0534
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发表时间：
2007-01-01
影响因子：
4.4
通讯作者：
Ishida, Susumu
中科院分区：
文献类型：
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作者：
Satofuka, Shingo;Ichihara, Atsuhiro;Ishida, Susumu
目的。最近的研究表明，抑制前肾素的非蛋白水解性激活可以显著抑制内毒素诱导的葡萄膜炎的眼部炎症。本研究的目的是探讨非蛋白水解性前肾素在缺血诱导的视网膜新生血管中是否起作用。方法：C57BL/6新生小鼠从出生后第7天到第12天在80%的氧气中饲养，然后对P17进行室内空气呼吸以诱导缺血诱导的视网膜新生血管。免疫组织化学方法检测活化的前肾小球蛋白及其受体的组织定位。给动物腹腔注射句柄区域肽(HRP)，这是一种对应于前肾素句柄区域的诱饵肽，它抑制前肾素受体介导的肾素-血管紧张素系统(RAS)的上调。用刀豆蛋白A凝集素灌流标记技术评估生理性和病理性视网膜新生血管的面积和附着在血管上的白细胞的数量。用RT-PCR和ELISA法检测视网膜组织中细胞间黏附分子(ICAM)-1、血管内皮生长因子(VEGF)、血管内皮生长因子受体(VEGFR)-1和VEGFR-2的表达和蛋白水平。与赋形剂或对照多肽处理的小鼠相比，HRP处理的小鼠的病理性视网膜新生血管显著减少，而非生理性新生血管显著减少。贴壁的白细胞数量也明显减少。HRP可显著抑制缺血性视网膜病变视网膜ICAM-1、VEGF、VEGFR-1和VEGFR-2的表达和蛋白水平，提示前肾素的非蛋白水解性激活通过与病理性新生血管相关的炎症过程选择性地促进病理性视网膜新生血管，而不是生理性新生血管。
PURPOSE. Recently, it was revealed that the inhibition of nonproteolytic activation of prorenin led to significant suppression of ocular inflammation in endotoxin-induced uveitis. The purpose of the present study was to investigate whether nonproteolytically activated prorenin plays a role in ischemia-induced retinal neovascularization.METHODS. C57BL/6 neonatal mice were reared in an 80% concentration of oxygen from postnatal (P) day 7 to P12, followed by room-air breathing to P17 to induce ischemia-initiated retinal neovascularization. Tissue localization of activated prorenin and prorenin receptor was examined by immunohistochemistry. Animals received intraperitoneal injections of handle-region peptide (HRP), a decoy peptide corresponding to the handle region of prorenin, which inhibits prorenin receptor-mediated upregulation of the renin-angiotensin system (RAS). A concanavalin A lectin perfusion-labeling technique was used to evaluate the areas of physiologic and pathologic retinal new vessels and the number of leukocytes adhering to the vasculature. Retinal mRNA expression and protein levels of intercellular adhesion molecule (ICAM)-1, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2 were examined by RT-PCR and ELISA.RESULTS. Retinal vessels in ischemic retinopathy eyes were positive for activated prorenin and prorenin receptor. Pathologic, but not physiologic, retinal neovascularization was significantly attenuated in HRP-treated mice compared with vehicle or control peptide-treated animals. The number of adherent leukocytes was also significantly reduced. Retinal mRNA expression and protein levels of ICAM-1, VEGF, VEGFR-1, and VEGFR-2 in ischemic retinopathy were also significantly suppressed by the application of HRP.CONCLUSIONS. The present findings suggest that nonproteolytic activation of prorenin selectively promotes pathologic, but not physiologic, retinal neovascularization through the inflammatory processes related to pathologic neovascularization.