Potential of Urinary AGT as a Novel Biomarker for Intrarenal RAS Activity in T1DM

尿液 AGT 作为 T1DM 肾内 RAS 活性的新型生物标志物的潜力

• 批准号: 8227361
• 负责人: Luis Gabriel Navar
• 金额: $ 22.58万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8227361
• 关键词: Address; Adolescent; Age; Angiotensin II; Angiotensinogen; Angiotensins; Animals; Biological Markers; Cardiovascular Diseases; Chronic Kidney Failure; Clinical; Collection; Data; Development; Diabetic Nephropathy; Disease; Economic Burden; Enzyme-Linked Immunosorbent Assay; Enzymes; Excretory function; Exhibits; Functional disorder; Gender; Human; Injury; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Laboratories; Lead; Link; Measurement; Measures; Messenger RNA; Methods; Monitor; Patients; Peptides; Play; Prospective Studies; Proteins; Rattus; Renal function; Renin; Renin-Angiotensin System; Reporting; Research Project Grants; Risk; Role; Technology; Time; Up-Regulation; Western Blotting; base; diabetic; health economics; improved; indexing; novel; olmesartan; prevent; receptor; success; translational study; urinary; young adult

DESCRIPTION (provided by applicant): Angiotensinogen (AGT) is the only known substrate for renin, which is the rate-limiting enzyme of the renin-angiotensin system (RAS). Because the levels of AGT are close to the Michaelis-Menten constant for renin, not only renin levels, but also AGT levels can dictate the activity of the RAS, and up-regulation of AGT levels may lead to increased angiotensin peptide formation and consequent renal injury. Enhanced intrarenal AGT mRNA and/or protein levels have been observed in diabetic animals. Thus, intrarenal AGT plays an important role in the development and progression of diabetic nephropathy. While there is evidence that the intrarenal RAS is stimulated in various diseases and pathophysiologic states, there are no means currently available to directly quantitate the magnitude of the activation of the intrarenal RAS. We previously reported that urinary excretion rates of AGT provide a specific index of intrarenal RAS status in angiotensin II-infused rats. To facilitate quantitative measurements, we recently developed a direct method to measure urinary AGT using human AGT enzyme-linked immunosorbent assays (ELISA). Using technology developed in our laboratory, based on several preliminary data described below, this clinical translational study will define and characterize the urinary AGT levels in juveniles and young adults with type 1 diabetes mellitus (T1DM). The overall hypothesis is that urinary AGT levels can be a novel biomarker of the intrarenal RAS status. In accord with this hypothesis, the following Specific Aims are targeted: 1) To establish a cutoff value of urinary AGT levels in juvenile control subjects and patients with T1DM, which will be used in Specific Aim 4. 2) To demonstrate that urinary AGT levels are higher in T1DM juveniles compared to that in age and gender-matched control subjects in a prospective study. 3) To demonstrate that urinary AGT levels are higher in T1DM juveniles with nephropathy compared to that in T1DM juveniles without nephropathy using GoKindD collection. 4) To demonstrate in T1DM juveniles that the high baseline of urinary AGT levels at the entry are causally linked to the progression of renal dysfunction and further increased urinary AGT levels, while renal function and urinary AGT levels are stable in patients with the low baseline of urinary AGT levels at the entry. The quantitative aspects of our ELISA approach allow us to compare data among subjects over time with ease. If the aims of the proposed study are achieved, the activated intrarenal RAS can be monitored by measuring urinary AGT levels in these patients. Therefore, this research project holds the potential to achieve the greatest impact for individualized patient management in DM. PUBLIC HEALTH RELEVANCE: Our overall hypothesis is that urinary angiotensinogen (AGT) levels are useful as a novel biomarker of the status of the intrarenal renin-angiotensin system (RAS) and potentially serve as a predictor of the risks for developing renal injury. If the aims of the proposed study are successful, the intrarenal RAS can be monitored by measuring urinary AGT levels in patients. Therefore, this research project has the potential to achieve significant impact for individualized patient management in patients with type 1 diabetes using urinary AGT as a biomarker to optimize treatments with RAS blockades, and the success of this proposed study can lead to improved health and economic burden of chronic kidney disease and cardiovascular disease in the US.

描述（由申请人提供）：血管紧张素原（AGT）是唯一已知的肾素底物，肾素是肾素-血管紧张素系统（RAS）的限速酶。由于 AGT 水平接近肾素的米氏常数，因此不仅肾素水平，AGT 水平也可以决定 RAS 的活性，并且 AGT 水平的上调可能导致血管紧张素肽形成增加，从而导致肾损伤。受伤。在糖尿病动物中观察到肾内 AGT mRNA 和/或蛋白质水平增强。因此，肾内AGT在糖尿病肾病的发生和发展中起着重要作用。虽然有证据表明肾内 RAS 在各种疾病和病理生理状态下受到刺激，但目前没有方法可以直接定量肾内 RAS 激活的程度。我们之前报道过，AGT 的尿排泄率提供了血管紧张素 II 输注大鼠肾内 RAS 状态的特定指标。为了便于定量测量，我们最近开发了一种使用人 AGT 酶联免疫吸附测定 (ELISA) 测量尿液 AGT 的直接方法。这项临床转化研究将使用我们实验室开发的技术，基于下述的几个初步数据，定义和表征患有 1 型糖尿病 (T1DM) 的青少年和年轻人的尿 AGT 水平。总体假设是尿 AGT 水平可以作为肾内 RAS 状态的新生物标志物。根据这一假设，有以下具体目标： 1) 建立青少年对照受试者和 T1DM 患者尿 AGT 水平的临界值，该临界值将用于具体目标 4。 2) 证明尿 AGT 水平在一项前瞻性研究中，与年龄和性别匹配的对照受试者相比，T1DM 青少年的 T1DM 水平更高。 3) 使用 GoKindD 收集证明，与无肾病的 T1DM 青少年相比，患有肾病的 T1DM 青少年的尿液 AGT 水平较高。 4) 在T1DM青少年中证明，入组时尿AGT水平的高基线与肾功能障碍的进展以及尿AGT水平进一步升高存在因果关系，而在低基线的患者中，肾功能和尿AGT水平是稳定的。入口处尿液 AGT 水平。我们的 ELISA 方法的定量方面使我们能够轻松比较受试者之间随时间变化的数据。如果拟议研究的目标得以实现，则可以通过测量这些患者的尿液 AGT 水平来监测激活的肾内 RAS。因此，该研究项目有可能对糖尿病患者的个体化管理产生最大的影响。 公共健康相关性：我们的总体假设是，尿血管紧张素原 (AGT) 水平可作为肾内肾素-血管紧张素系统 (RAS) 状态的新型生物标志物，并有可能作为发生肾损伤风险的预测因子。如果拟议研究的目标成功，则可以通过测量患者尿液 AGT 水平来监测肾内 RAS。因此，该研究项目有可能对 1 型糖尿病患者的个体化患者管理产生重大影响，使用尿 AGT 作为生物标志物来优化 RAS 阻断的治疗，并且该研究的成功可以改善健康和经济负担美国慢性肾脏病和心血管疾病的发病率。