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: 6841512
• 负责人: JULIE R. INGELFINGER
• 金额: $ 4.95万
• 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/6841512
• 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; shiga toxin; 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.

描述（改编自应用程序）