GENETIC VARIANTS IN RENIN ANGIOTENSIN SYSTEM IN PEDIATRIC RENAL DISEASE

肾素血管紧张素系统（RAS）已被公认为具有 在心血管和肾脏疾病中起着至关重要的作用。 最有说服力 是动物模型和临床研究中积累的数据， 肯定拮抗抗氧化剂的肾保护作用的试验 血管紧张素II（Ang II）的生成或作用。 有趣的是，RAS 活性可以通过RAS组分的遗传变异来调节。 特别地，在基因组中的插入/缺失多态性（I/D）可以被检测到。 人血管紧张素I转换酶（ACE）基因影响 循环ACE水平;此外，纯合缺失（DD） 可预测多种心血管疾病和进行性恶化 在一些肾小球疾病中，包括伊加和糖尿病 肾病 我们的项目将测试遗传的假设 RAS变异，特别是ACE I/D变异， 非肾小球损伤中的进行性肾损害，即 先天性尿路病，其中RAS具有关键作用。 此实体 儿童肾损害的重要原因。 我们还计划 确定遗传变异影响下游的途径 进行性肾损伤的关键事件。 考虑到 ACE I/D对ACE活性影响的显著异质性 在器官之间，我们假设有一个更紧密的联系 ACE基因多态性与肾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-mediated 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剂（派）和纤溶酶原激活物组织抑制剂 金属蛋白酶组织抑制剂（TIMP），局部肾血管紧张素转换酶， (and下游调节剂派/TIMP）在肾脏中是关键的。 对损伤的反应将直接在遗传学上进行研究。 基因工程小鼠的特点是区域差异水平 ACE活性。 最后，人类细胞系的诱变研究将 定义一个假定的调节元件的功能结果 在ACE I/D位点。

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.