RENIN-ANGIOTENSIN SYSTEM IN EXPERIMENTAL DIABETES

肾素-血管紧张素系统(RAS)参与了 糖尿病肾小球病变的发病机制。这个项目的目标是 探讨全身和肾内的关系和相互作用 肾素-血管紧张素系统，以定义其不同的调节 机制，并确定这种激素的特定部位的作用 系统在调节肾小球血流动力学功能中的作用 糖尿病肾病。基本原理：(1)虽然血浆肾素正常， 糖尿病患者循环血管紧张素II水平升高 大鼠，表明系统肾素-血管紧张素轴不一致 (RAS)。这一新问题的起源、调解人和监管后果 已确认的异常情况仍有待调查。(2)生化、分子 生物学和免疫组织化学研究都表明 肾内RAS活性与血浆RAS、AS不成比例 以及肾脏RAS组分的重新分布。更精确 需要对各种RAS组件进行本地化和量化 确定他们特定于站点的角色。(3)尽管RAS封锁影响 肾功能，主要血流动力学问题(传入小动脉 血管扩张)必须受到其他激素系统的影响。 一般假设：高水平的血管紧张素转换酶II是活动增加的结果 非经典加工途径，和/或组织的贡献 可能受到相互关联的血管扩张剂的影响。 肾内RAS局部活动增强，特别是在 肾小球和肾血管系统对局部血流动力学的影响 监管。然而，RAS活动的增加也提供了刺激 反调节血管扩张剂系统(激肽释放酶-激动素系统和 内皮细胞衍生的松弛因子)，它扩张传入小动脉 从而也有助于血流动力学的适应。特定的 目的：(1)对蚀变RAS组分加工场地(S)进行定位， 通过确定它们是否由改变的处理路径引起， 肾外组织RAS不成比例的贡献，和/或 改变的降解；(2)确定肾内血管紧张素Ⅱ的形成 和作用均在糖尿病肾脏中增加，而全身性作用 Ang II在调节肾内RAS中的水平；(3)确定 Ang II刺激激肽释放酶-激动素系统的活性，并 内皮衍生的松弛因子，并测定 这些血管扩张剂和RAS之间的相互关系 血液动力学和荷尔蒙调节。为了实现这些目标，我们将利用 集生化、分子生物学、免疫组织化学和 生理学方法。将这些调查工具结合在一起将 为了解其发病机制提供了一种新颖而有力的途径 糖尿病微血管病变，潜在地允许更具特异性和 有效预防这一终末期肾病的主要原因和 发病率。

The renin-angiotensin system (RAS) has been implicated in the pathogenesis of diabetic glomerulopathy. The goal of this project is to explore the relationships and interactions of the systemic and intrarenal renin-angiotensin systems, to define their different regulatory mechanisms, and to determine the site-specific roles of this hormonal system in the modulation of glomerular hemodynamic function in the diabetic kidney. Rationale: (1) Though plasma renin is normal, circulating levels of Angiotensin II (Ang II) are elevated in diabetic rats, indicating discordance of the systemic renin-angiotensin axis (RAS). Origins, mediators, and regulatory consequences of this newly recognized abnormality remain to be explored. (2) Biochemical, molecular biologic, and immunohistochemical studies all indicate heightened activity of the intrarenal RAS, disproportionate to the plasma RAS, as well as redistribution of renal RAS components. More precise localization and quantitation of various RAS components is required to determine their site-specific roles. (3) Though RAS blockade influences renal function, the primary hemodynamic problem (afferent arteriolar vasodilation) must be under the influence of other hormonal systems. General hypothesis: High Ang II levels result from increased activity of non-classical processing pathways, and/or contributions of tissue processing pathways, and may be influenced by interrelated vasodilators. Localized heightened activity of the intrarenal RAS, particularly in the glomeruli and renal vasculature, contributes to local hemodynamic regulation. However, increased RAS activity also provides a stimulus to counter-regulatory vasodilator systems (the kallikrein-kinin system and endothelial derived relaxing factor), which dilate the afferent arteriole and thereby also contribute to the hemodynamic adaptations. Specific aims: (1) To localize the site(s) of altered RAS component processing, by determining whether they result from altered processing pathways, disproportionate contribution of the extrarenal tissue RAS, and/or altered degradation; (2) to determine whether intrarenal Ang II formation and action are increased in the diabetic kidney, and the role of systemic Ang II levels in regulating the intrarenal RAS; (3) to determine whether Ang II stimulates activity of the kallikrein-kinin system and endothelial-derived relaxing factor, and to determine the interrelationships among these vasodilators and the RAS in terms of hemodynamic and hormonal regulation. To achieve these aims, we will use an integrated biochemical, molecular biologic, immunohistochemical, and physiologic approach. Joining these investigative tools together will provide a novel and powerful approach to understanding the pathogenesis of diabetic microangiopathy, potentially allowing more specific and effective prevention of this leading cause of end stage renal disease and morbidity.