Regulation of glomerular permeability by VEGF

终末期肾衰竭在发达国家正变得越来越普遍--在英国，平均每年增加5%。英国37,500名终末期肾病患者是一个巨大的经济负担，占0.06%人口消费的整个卫生预算的3%。许多肾脏疾病源于肾脏滤器或肾小球的损伤。在健康中，这些过滤单元对水和小分子(促进尿液的产生)具有很强的渗透性，但对蛋白质(这是需要保存的重要分子)的渗透性很低。因此，过滤器对不同物质具有不同的渗透性。许多肾脏疾病的特点是通透性紊乱和蛋白质渗入尿液。此外，由于尚不清楚的原因，尿液中蛋白质的存在最近也被确定为心血管疾病(中风、心脏病发作等)的非常强的预测因子。肾小球含有细胞(足细胞)，可产生调节肾小球功能的血管内皮生长因子(VEGF)等分子。我们打算研究两种形式的血管内皮生长因子-血管内皮生长因子165和血管内皮生长因子165b在这些分子的表达可能受到控制的疾病模型中的作用。此外，由于结构预测功能，我们将在电子显微镜水平上三维重建这些肾小球。这项研究可能允许开发新的策略来维持正常或重建正常的通透性。因此，这不仅对肾病患者，而且对那些有心血管疾病风险的人，都可能产生深远的影响，为卫生服务提供者带来巨大的经济利益。

End stage kidney failure is becoming increasingly common across the developed world - averaging a 5% increase per year in the UK. The 37,500 UK patients with end stage kidney disease represent a significant financial burden, representing 3% of the entire health budget consumed by 0.06% of the population. Many kidney diseases stem from injury to the kidney filters or glomeruli. In health these filtering units are very permeable to water and small molecules (promoting the production of urine) but have a low permeability to proteins (which are important molecules to conserve). Thus the filters have a differential permeability to different substances. Many kidney diseases are characterised by a derangement in permeability and leakage of protein into the urine. Furthermore, for reasons that are not clear, the presence of protein in the urine has also recently been identified as a very strong predictor of cardiovascular disease (stokes, heart attacks etc). The glomeruli contains cells (podocytes) that produce molecules such as Vascular Endothelial Growth Factors (VEGF) that regulate glomerular function. We intend to study the effects of two forms of VEGF - VEGF165 and VEGF165b in models of disease in which expression of these molecules may be controlled. Furthermore, since structure predicts function, we will reconstruct these glomeruli in 3D at the electron microscope level. This study may allow the development of novel strategies to maintain normal or re-establish normal permeability. This may therefore have profound implications not only for kidney patients but also those at risk of cardiovascular disease producing significant financial benefits for health service providers.