Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
PLoS One. 2017 Dec 14;12(12):e0189696. doi: 10.1371/journal.pone.0189696. eCollection 2017.
(Pro)renin receptor [(P)RR], a new component of the tissue renin-angiotensin system (RAS), plays a crucial role in inflammation and angiogenesis in the eye, thus contributing to the development of proliferative diabetic retinopathy (PDR). In this study, we investigated systemic factors related to plasma levels of soluble form of (P)RR [s(P)RR] in patients with PDR. Twenty type II diabetic patients with PDR and 20 age-matched, non-diabetic patients with idiopathic macular diseases were enrolled, and plasma levels of various molecules were measured by enzyme-linked immunosorbent assays. Human retinal microvascular endothelial cells were stimulated with several diabetes-related conditions to evaluate changes in gene expression using real-time quantitative PCR. Of various systemic parameters examined, the PDR patients had significantly higher blood sugar and serum creatinine levels than non-diabetic controls. Protein levels of s(P)RR, prorenin, tumor necrosis factor (TNF)-α, complement factor D (CFD), and leucine-rich α-2-glycoprotein 1 (LRG1) significantly increased in the plasma of PDR subjects as compared to non-diabetes, with positive correlations detected between s(P)RR and these inflammatory molecules but not prorenin. Estimated glomerular filtration rate and serum creatinine were also correlated with plasma s(P)RR, but not prorenin, levels. Among the inflammatory molecules correlated with s(P)RR in the plasma, TNF-α, but not CFD or LRG1, application to retinal endothelial cells upregulated the mRNA expression of (P)RR but not prorenin, while stimulation with high glucose enhanced both (P)RR and prorenin expression. These findings suggested close relationships between plasma s(P)RR and diabetes-induced factors including chronic inflammation, renal dysfunction, and hyperglycemia in patients with PDR.
（前）肾素受体 [(P)RR]，组织肾素-血管紧张素系统 (RAS) 的新组成部分，在眼睛的炎症和血管生成中发挥关键作用，从而促进增殖性糖尿病视网膜病变 (PDR) 的发展。在这项研究中，我们研究了与 PDR 患者血浆可溶性形式 (P)RR [s(P)RR] 水平相关的全身因素。纳入 20 例 2 型糖尿病伴 PDR 患者和 20 例年龄匹配的特发性黄斑病变非糖尿病患者，并通过酶联免疫吸附试验测量各种分子的血浆水平。用人视网膜微血管内皮细胞用几种与糖尿病相关的条件刺激，使用实时定量 PCR 评估基因表达的变化。在所检查的各种全身参数中，PDR 患者的血糖和血清肌酐水平明显高于非糖尿病对照组。与非糖尿病患者相比，PDR 患者的血浆中 s(P)RR、前肾素、肿瘤坏死因子 (TNF)-α、补体因子 D (CFD) 和富含亮氨酸的α-2-糖蛋白 1 (LRG1) 的蛋白水平显著升高，并且检测到 s(P)RR 与这些炎症分子之间存在正相关，但与前肾素无关。估计肾小球滤过率和血清肌酐与血浆 s(P)RR 相关，但与前肾素无关。在与血浆 s(P)RR 相关的炎症分子中，TNF-α，但不是 CFD 或 LRG1，应用于视网膜内皮细胞上调 (P)RR 而不是前肾素的 mRNA 表达，而高葡萄糖刺激增强了 (P)RR 和前肾素的表达。这些发现表明，在 PDR 患者中，血浆 s(P)RR 与包括慢性炎症、肾功能障碍和高血糖在内的糖尿病诱导因素之间存在密切关系。
