GENETIC VARIANTS IN RENIN ANGIOTENSIN SYSTEM IN PEDIATRIC RENAL DISEASE

肾素血管紧张素系统(RAS)被公认为具有 在心血管和肾脏疾病中起着至关重要的作用。最有说服力 在动物模型和临床中是否有积累的数据？ 肯定拮抗作用的肾脏保护作用的试验 血管紧张素II(Ang II)的产生或作用。有趣的是，RAS 活性可以通过RAS组分的遗传变异来调节。 特别是，插入/缺失多态(I/D)在 人血管紧张素转换酶(ACE)基因影响血管紧张素转换酶 循环血管紧张素转换酶水平；此外，纯合缺失(DD) 预测了几种心血管疾病和进行性恶化 在一些肾小球疾病中，包括IgA和糖尿病 肾病。我们的项目将检验这样一个假设，即基因 RAS的变化，特别是ACE I/D变化，预测 非肾小球损害的进行性肾损害，即 先天性尿路疾病，RAS在其中起着至关重要的作用。该实体是 这是导致儿童肾脏损害的重要原因。我们还计划进一步 确定基因变异影响下游的途径 进行性肾损害的关键事件。鉴于 ACE I/D对ACE活性影响的明显异质性 在器官之间，我们假设有一个更紧密的联系 血管紧张素转换酶基因多态性与肾脏(与全身)血管紧张素转换酶活性之间的关系。 此外，ACE I/D驱动其他ANG中介的目的 在组织损伤中重要的因素，如蛋白酶，例如， 纤溶酶原激活物抑制物(PAI)和组织抑制物 金属蛋白酶(TIMP)，局部肾脏ACE的假说 (和下游调节物PAI/TIMP)在肾脏中起关键作用 对伤害的反应将直接在遗传学上进行研究 基因工程小鼠的特征是不同地区水平的差异 王牌活动。最后，对人类细胞系的突变研究将 定义假定的监管要素的功能后果 在ACE I/D轨迹中。

Renin angiotensin system (RAS) is well established as having a crucial role in cardiovascular and renal diseases. Most persuasive are the accumulating data in animal models as well as in clinical trials affirming the renoprotective effects of antagonizing angiotensin II (Ang II) generation or actions. Interestingly, RAS activity can be modulated by genetic variations of RAS components. In particular, an insertion/deletion polymorphism (I/D) in the human angiotensin I converting enzyme (ACE) gene affects the level of circulating ACE; moreover, homozygous deletion (DD) predicts several cardiovascular disease and progressive deterioration in some glomerular disease, including IgA and diabetic nephropathies. Our projects will test the hypothesis that genetic variations in RAS, particularly the ACE I/D variant, predicts progressive renal damage in a non-glomerular injury, namely congenital uropathies, where RAS has a crucial role. This entity is an important cause of renal damage in children. We further plan to define pathways by which the genetic variant influences downstream events pivotal in progressive renal damage. In view of the apparant heterogeneity in the impact of ACe I/D on ACE activity among organs, we hypothesize that there is a tighter association between ACE polymorphism and renal (vs systemic) ACE activity. Moreover, the purpose that ACE I/D drives other Ang-mediated factors important in tissue damage such as proteinases, e.g., plasminogen activator inhibitor (PAI) and tissue inhibitor of metalloproteinase (TIMP), The hypothesis that local renal ACE (and downstream modulators PAI/TIMP) is pivotal in the renal response to injury will be directly studies in a genetically engineered mouse characterized by regional difference in levels of ACE activity. Finally, mutagenesis studies in human cell lines will define the functional consequence of a putative regulatory element in the ACE I/D locus.