Uncoupling of VEGF with NO as a mechanism for diabetic nephropathy
Uncoupling of VEGF with NO as a mechanism for diabetic nephropathy
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DOI：
10.1016/j.diabres.2008.09.030
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发表时间：
2008-11-13
影响因子：
5.1
通讯作者：
Nakagawa, Takahiko
中科院分区：
文献类型：
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作者：
Nakagawa, Takahiko
VEGF对多种非糖尿病性肾脏疾病具有保护作用。然而，尽管VEGF高，但VEGF在介导糖尿病肾病的发展/进展方面表现出有害作用。在非糖尿病疾病中，VEGF的保护作用可能主要在于其刺激内皮细胞中一氧化氮产生的能力。然而，已知糖尿病患者的一氧化氮生物利用度降低，表明糖尿病状态不允许高VEGF导致NO生物利用度的全部增加。因此，VEGF可参与NO非依赖性途径，对血管系统产生有害影响。因此，我们假设，解偶联血管内皮细胞生长因子与内皮细胞NO可以是一种机制，其中血管内皮生长因子导致糖尿病nephropathies.We发现，糖尿病eNOS敲除（KO）小鼠表现出masangiolysis，肾小球毛细血管微动脉瘤，Kimmelstiel-Wilson样结节性病变，异常血管生成和显着的巨噬细胞浸润，除了系膜扩张和增厚GBM，所有这些都类似于人类糖尿病肾病。有趣的是，这些病变与肾脏VEGF表达的增加有关，表明VEGF与内皮NO的解偶联可能是一种机制。我们的体外实验证明，VEGF诱导的内皮细胞增殖被NO阻断（用LNAME）增强，并被外源性NO给药抑制，而响应于VEGF的巨噬细胞迁移被外源性NO抑制，这表明解偶联条件可能导致异常的血管生成和巨噬细胞浸润。(C)2008爱思唯尔爱尔兰有限公司保留所有权利。
VEGF plays protective roles on a variety of non-diabetic renal diseases. However, in VEGF exhibits deleterious roles to mediate the development/progression of diabetic nephropathy in spite of high VEGF. The protective role of VEGF could be predominantly on its ability to stimulate nitric oxide production in endothelial cell in non-diabetic disease. However, it has been known that nitric oxide bioavailability is reduced in diabetes, indicating that diabetic status does not allow high VEGF to lead to all increase in NO bioavailability. As a result, VEGF could engage to NO-independent pathway, and cause deleterious effects on vascular system. Thus, we have hypothesized that uncoupling VEGF with endothelial NO can be a mechanism by which VEGF causes diabetic nephropathy.We found that diabetic eNOS knockout (KO) mice exhibit masangiolysis, glomerular capillary microaneurysm, Kimmelstiel-Wilson-like nodular lesions, abnormal angiogenesis and a marked macrophage infiltration in addition to mesangial expansion and thickening GBM, all of that resemble human diabetic nephropathy. Interestingly these lesions were associated with an increase in renal VEGF expression, suggesting uncoupling of VEGF with endothelial NO could be a mechanism. Compatibly, our in vitro experiments demonstrated that VEGF-induced endothelial cell proliferation was enhanced by NO blocking (with LNAME) and suppressed by exogenous NO administration whereas macrophage migration in response to VEGF was inhibited by exogenous NO, suggesting that uncoupling condition could cause abnormal angiogenesis and macrophage infiltration. (C) 2008 Elsevier Ireland Ltd. All rights reserved.