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）是肾素的唯一已知底物，肾素是肾素-血管紧张素系统（RAS）的限速酶。由于AGT的水平接近于肾素的米氏常数，因此不仅肾素水平，而且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和随后的肾损伤。在糖尿病动物中观察到肾内AGT mRNA和/或蛋白水平增加。因此，肾内AGT在糖尿病肾病的发生和发展中起重要作用。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，但目前还没有直接定量肾内RAS激活程度的方法。我们以前报道，尿AGT排泄率提供了一个具体的指标，肾内RAS状态血管紧张素II输注大鼠。为了便于定量测量，我们最近开发了一种直接的方法来测量尿AGT使用人AGT酶联免疫吸附试验（ELISA）。使用我们实验室开发的技术，基于以下描述的几个初步数据，这项临床转化研究将定义和表征青少年和年轻人1型糖尿病（T1 DM）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。雅阁这一假设，目标如下：1）确定青少年对照受试者和T1 DM患者的尿AGT水平临界值，该临界值将用于具体目标4。2)在一项前瞻性研究中，证明与年龄和性别匹配的对照受试者相比，T1 DM青少年的尿AGT水平较高。3)使用GoKindD采集，证明患有肾病的T1 DM青少年的尿AGT水平高于不患有肾病的T1 DM青少年。4)在T1 DM青少年中证明入组时尿AGT水平的高基线与肾功能不全进展和尿AGT水平进一步升高存在因果关系，而入组时尿AGT水平低基线的患者的肾功能和尿AGT水平稳定。我们的ELISA方法的定量方面使我们能够轻松地比较受试者之间的数据。如果达到了本研究的目的，则可以通过测定这些患者的尿AGT水平来监测肾内RAS的活化。因此，本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。 公共卫生相关性：我们的总体假设是，尿血管紧张素原（AGT）水平是有用的，作为一种新的生物标志物的状态，肾内的肾素-血管紧张素系统（RAS），并可能作为一个预测的风险发展为肾损伤。如果所提出的研究的目的是成功的，肾内RAS可以通过测量患者的尿AGT水平进行监测。因此，这项研究项目有可能对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，以优化RAS阻断治疗，这项拟议研究的成功可能会改善美国慢性肾脏疾病和心血管疾病的健康和经济负担。