Role of the VEGF-A signaling pathway in the glomerulus: Evidence for crosstalk between components of the glomerular filtration barrier
Role of the VEGF-A signaling pathway in the glomerulus: Evidence for crosstalk between components of the glomerular filtration barrier
复制标题
DOI：
10.1159/000101798
复制
发表时间：
2007-01-01
影响因子：
--
通讯作者：
Quaggin, Susan E.
中科院分区：
文献类型：
--
作者：
Eremina, Vera;Baelde, Hans J.;Quaggin, Susan E.
背景/目的：血管内皮生长因子是血管生成和血管通透性的主要调节因子[Carmeliet et al.: Nature 1996；380: 435 - 439)。足细胞，肾小球滤过屏障的最外层，产生大量VEGF-A。VEGF- a水平在肾小球疾病中发生改变的观察，子痫前期与循环可溶性VEGF受体水平升高之间的联系的确定，以及抗VEGF疗法进入临床领域，引起了人们对VEGF- a在肾小球中的功能作用的强烈兴趣。方法：已经进行了各种研究来解决VEGF-A信号在肾小球中的作用。其中包括对人类肾活检表达模式的描述，剖析旁分泌与自分泌信号作用的细胞培养研究，以及使用药理学、生物学或遗传学方法在动物模型中操纵VEGF-A表达。结果：发育中的肾小球对VEGF-A具有高度的剂量敏感性，VEGF-A表达的微小降低会导致小鼠肾小球结构和功能的深刻变化。VEGF抑制剂的使用与动物模型中的肾小球内皮损伤和患者的蛋白尿有关，这表明局部VEGF- a的产生也是维持这种特殊血管床所必需的。结论：肾小球滤过屏障（glomerular filtration barrier， GFB）的形成和维持需要VEGF-A信号的严格调控，并强调足细胞-内皮细胞串扰在肾小球中的作用。各种VEGF-A亚型的相对贡献，体内自分泌信号的作用，以及调节VEGF-A在肾小球中组成性表达、储存和传递的因素和机制的鉴定仍在研究中。版权所有(c) 2007 S. Karger AG，巴塞尔。
Background/Aims: Vascular endothelial growth factor is a major regulator of angiogenesis and vascular permeability [Carmeliet et al.: Nature 1996; 380: 435-439]. The podocyte, the outermost layer of the glomerular filtration barrier, produces large amounts of VEGF-A. The observation that levels of VEGF-A are altered in glomerular diseases, the identification of a link between pre-eclampsia and elevated levels of a circulating soluble VEGF receptor, and the entry of anti-VEGF therapies into the clinical arena have generated intense interest in the functional role of VEGF-A in the glomerulus. Methods: A variety of studies have been performed to address the role of VEGF-A signaling in the glomerulus. These include descriptions of expression patterns in human renal biopsies, cell culture studies to dissect paracrine versus autocrine signaling roles, and manipulation of VEGF-A expression in animal models using pharmacologic, biologic or genetic approaches. Results: Exquisite dosage sensitivity to VEGF-A exists in the developing glomerulus as small reductions in the expression of VEGF-A lead to profound changes in glomerular structure and function in mice. The use of VEGF inhibitors is associated with damage to the glomerular endothelium in animal models and proteinuria in patients, suggesting that local VEGF-A production is also required for maintenance of this specialized vascular bed. Conclusions: Tight regulation of VEGF-A signaling is required for development and maintenance of the glomerular filtration barrier (GFB) and emphasizes the role of podocyte-endothelial crosstalk in the glomerulus. The relative contributions of various VEGF-A isoforms, the role of autocrine signaling in vivo and identification of factors and mechanisms that regulate constitutive expression, storage and delivery of VEGF-A in the glomerulus are still under investigation. Copyright (c) 2007 S. Karger AG, Basel.