PROXIMAL TUBULE ANGIOTENSINS--HEMOLYTIC UREMIC SYNDROME

近端小管血管紧张素--溶血性尿毒症综合征

• 批准号: 6288357
• 负责人: JULIE R. INGELFINGER
• 金额: $ 25.21万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6288357
• 关键词: angiotensins; animal tissue; blood flow measurement; clinical research; cytokine; hemolytic anemia; human tissue; interleukin 6; pathologic process; plasminogen activator inhibitors; protein biosynthesis; renal failure; renal tubule; transforming growth factors

DESCRIPTION (adapted from the application) Most studies of hemolytic uremic syndrome (HUS), a leading cause of acute renal failure in children, have focused on mechanisms of thrombotic microangiopathy and endothelial injury. However, until recently, consideration of the renal tubule as a site for primary damage by shiga-like toxin [Stx] has been largely tangential. It has now been reported that human proximal tubule cells [PTCs] are exquisitely sensitive to damage by Stx. Much work on pathogenesis has shown that Stx-related disease leads to abnormalities in coagulation factors, increased shear forces, oxidant injury, platelet activation, rbc injury, with involvement of multiple cytokines and vasoactive substances. While much attention has focused on changes in endothelin, NO, and vasodilator substances, little has been paid to the potential role of the renin-angiotensin system [RAS] in modulating the severity of HUS. In recent years, the interaction of the RAS with coagulation factors and cytokines has been recognized as important in both normal and pathophysiologic states. This application will focus on the unique role of the PTC tissue RAS, hypothesizing that local angiotensins amplify the effects of Stx in PTC, resulting in further injury. Thus, we will define the roles of the local proximal tubular RAS in HUS. We hypothesize that Stx-induced proximal tubule cell [PTC] injury initiates a pathologic series of events in which the RAS and the coagulation cascade interact as follows: PTC injury results in heightened Ang II generation. Altered glomerular and tubular shear forces lead to impairment of tubular fluid flow, accumulation of debris with rbc and leukocytes with near stasis, and even hypoxia. Angiotensins in this milieu in the presence of Stx and leukocyte and PT-derived cytokines [e.g., IL-1, TNF], favor PTC expression of tissue factor [TF, present in PT], PAI-1 and other pro-fibrotic factors. Furthermore, TF in the tubule may become further upregulated in view of exposure of PTC to blood products due to glomerular injury. Interrupting these interactions may abrogate or mitigate Stx-induced damage. The specific aims of this application are: 1. To demonstrate that Stx enhances the expression of the local RAS in proximal tubule cells [PTC], as well as in glomerular endothelial and mesangial cells, which, in turn, modulates tissue factor PAI-1, and cytokine production, contributing to tubular damage in HUS. Preliminary data suggest that Stx increases angiotensinogen and angiotensin converting enzyme (ACE) generation in PTCs, which are exquisitely sensitive to Stx 2. To demonstrate that Stx-induced RAS, in turn increases local TF, PAI-1 and cytokine production, contributing to tubular damage in HUS. We hypothesize that Stx-induced PTC injury is modulated by RAS, coagulation pathway and cytokine interaction, and influences PT functions. We will examine PTC under static and flow conditions, alone and in proximity to glomerular endothelial and mesangial cells; we will concomitantly study tissues from the baboon model of Stx-induced HUS using rheologic techniques and molecular studies. 3. To demonstrate abrogation of Stx-induced injury in PTC by blocking the interaction of angiotensins, shiga toxin, and the coagulation pathway. Using the same systems, the interaction of the RAS, coagulation factors and cytokines will be blocked sequentially and specifically in order to define the mechanism of these interactions. It is anticipated that specific blockade may lead to strategies with clinical relevance for the possible prevention or amelioration of HUS.

说明(改编自应用程序) 大多数关于溶血性尿毒症综合征(HUS)的研究，这是急性肾脏的主要原因 失败的儿童，一直专注于血栓性微血管病变的机制 和血管内皮损伤。然而，直到最近，考虑到肾脏 小管作为志贺样毒素[STX]的初级损伤部位，在很大程度上 切线。现已报道人近端小管细胞[PTCs] 对STX造成的伤害非常敏感。许多关于发病机制的研究表明 STX相关疾病会导致凝血因子异常， 剪切力增加，氧化损伤，血小板激活，红细胞损伤， 多种细胞因子和血管活性物质的参与。虽然有很多 人们的注意力集中在内皮素、一氧化氮和血管扩张物质的变化上， 肾素-血管紧张素系统的潜在作用尚未引起足够的重视。 [RAS]调节HUS的严重程度。近年来，中美之间的互动 具有凝血因子和细胞因子的RAS已被认为是重要的 在正常和病理生理状态下。此应用程序将重点放在 PTC组织RAS的独特作用，假设局部血管紧张素 放大STX在PTC中的作用，导致进一步的伤害。因此，我们将 明确局部近端小管RAS在HUS中的作用。我们假设 STX诱导的近端小管细胞[PTC]损伤引发一系列病理变化 RAS和凝固级联相互作用的事件如下：PTC 损伤会导致Ang II代的增加。肾小球和肾小管改变 剪切力导致管状流体流动受损，泥石堆积 红细胞和白细胞几近停滞，甚至缺氧。血管紧张素-2 在STX、白细胞和PT衍生的细胞因子存在的情况下 [例如，IL-1、TNF]，有利于组织因子[Tf，存在于PT]的PTC表达， PAI-1等促纤维化因子。此外，小管中的Tf可能会变成 鉴于PTC因以下原因暴露于血液产品而进一步上调 肾小球损伤。中断这些互动可能会废除或减轻 STX引起的损伤。本申请的具体目的是：1. 证明STX增强了近端局部RAS的表达 肾小管细胞[PTC]，以及肾小球内皮细胞和系膜细胞， 它反过来调节组织因子PAI-1和细胞因子的产生， 导致HUS的肾小管损伤。初步数据显示，STX 增加血管紧张素原和血管紧张素转换酶(ACE)的生成 对STX非常敏感的PTC。为了证明STX诱导 RAS进而增加局部TF、PAI-1和细胞因子的产生，有助于 HUS的肾小管损伤。我们假设STX诱导的PTC损伤是调制的 通过RAS、凝血途径和细胞因子相互作用影响PT 功能。我们将研究静态和流动条件下的PTC，单独和在 接近肾小球内皮细胞和系膜细胞；我们将同时 用流变学方法研究STX诱导的恒河猴模型的组织 技术和分子研究。3.证明STX诱导的废止作用 阻断血管紧张素、志贺毒素和血管紧张素转换酶的相互作用对PTC的损伤 凝血途径。使用相同的系统，RAS的交互作用， 凝血因子和细胞因子将被顺序和特异性地阻断 以确定这些相互作用的机制。预计 特定的阻断可能导致具有临床相关性的策略 可能预防或改善HUS。