Urinary Renin Angiotensin System in Diabetes

 描述(由申请人提供)：肾脏肾素-血管紧张素系统(RAS)的激活有助于糖尿病肾病的发展。这一概念是基于间接证据和RAS阻滞剂的已知治疗益处。我们推测，1型糖尿病患者尿中血管紧张素原(AOG)和肾素的升高将提供肾脏RAS激活的早期信号。参加糖尿病控制和并发症试验(DCCT)的1型糖尿病受试者的纵向随访为检验这一假设提供了一个独特的机会。我们建议同时评估DCCT研究参与者的尿样中的AOG和肾素，这些受试者在9年的纵向随访中没有接受RAS阻滞剂或任何其他抗高血压药物的治疗。我们将研究是否可以通过尿AOG和肾素水平来预测微量蛋白尿和大量蛋白尿范围内的蛋白尿的发展。此外，我们计划测量总AOG以及活动(完整)AOG。对于完整的AOG的测量，将使用一种新的ELISA法。完整的(或活跃的)AOG反映了肾素裂解比总AOG更好地形成Ang I的潜力，根据完整AOG与总AOG的比率可以推断在这一过程中消耗的AOG的量。尿肾素的调节似乎与血浆中的肾素不同，在糖尿病患者中会增加。因此，与糖尿病患者血浆肾素活性降低不同，尿液肾素活性可能升高，反映肾脏RAS过度活跃。最近在肾脏中发现了一条旁分泌信号通路，通过该通路，高水平的葡萄糖可以触发肾素的释放。我们假设，与传统的胰岛素治疗组相比，DCCT参与者强化胰岛素治疗提供的改善代谢控制对肾脏RAS产生了更有效的下调作用，这将表现为尿液AOG和肾素水平的降低。研究的具体目的是：1.根据DCCT研究中1型糖尿病患者储存的尿样分析，明确正常白蛋白尿、微量白蛋白尿和大量白蛋白尿的1型糖尿病患者的尿RAS谱(AOG和肾素)。目的2.通过对DCCT研究中1型糖尿病患者储存的生物样本进行纵向追踪9年，以确定尿血管紧张素原和/或肾素的增加是否先于微量白蛋白尿和大量白蛋白尿的发展。目的3.根据DCCT研究中纵向随访9年的1型糖尿病患者储存的尿样分析，确定在正常蛋白尿、微量蛋白尿和大量蛋白尿的患者中，强化胰岛素治疗是否能改善血糖控制，降低尿AOG和/或肾素。

 DESCRIPTION (provided by applicant): Activation of the kidney renin-angiotensin system (RAS) contributes to the development of diabetic nephropathy. This notion is based on indirect evidence and the known therapeutic benefit of RAS blockers. We hypothesize that increased angiotensinogen (AOG) and renin in urine from subjects with type 1 diabetes will provide an early signature of kidney RAS activation. The longitudinal follow-up of subjects with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) offers a unique opportunity to test this hypothesis. We propose to evaluate AOG and renin concurrently in urine samples from participants in the DCCT study who were not treated with RAS blockers or any other anti-hypertensive medications during a 9 year longitudinal follow-up. We will examine the question of whether the development of albuminuria, both in the microalbuminuric and macroalbuminuric range, could be predicted by the levels of urinary AOG and renin. Moreover, we plan to measure total AOG as well as active (intact) AOG. For measurement of intact AOG a novel ELISA assay will be used. Intact (or active) AOG reflects the potential for the formation of Ang I by renin cleavage better than total AOG as measured by current assays and the amount of AOG consumed in the process can be inferred from the ratio of intact to total AOG. Urinary renin appears to be regulated differently from renin in plasma and is increased in diabetes. Thus, unlike plasma renin activity, which is decreased in diabetes, urinary renin may be increased and reflect an over-active kidney RAS. A paracrine signaling pathway in the kidney has been recently identified whereby high levels of glucose trigger the release of renin. We hypothesize that improved metabolic control, as provided by intensive insulin therapy in DCCT participants exerted a more effective down-regulatory effect on the kidney RAS as compared to the conventional insulin therapy arm and that this will be manifested by reduced levels of urinary AOG and renin. The specific aims are: Aim 1. To define the urine RAS profile (AOG and renin) of type 1 diabetes with normoalbuminuria, microalbuminuria and macroalbuminuria based on the analysis of stored urine biosamples from subjects with type 1 diabetes in the DCCT study. Aim 2. To determine whether an increase in urinary angiotensinogen and/or renin antedate the development of micro-albuminuria and macroalbuminuria based on the analysis of stored biosamples from subjects with type 1 diabetes in the DCCT study followed longitudinally for 9 years. Aim 3. To determine if improved glycemic control provided by intensive insulin therapy in subjects with normo- albuminuria, micro-albuminuria and macroalbuminuria reduces urinary AOG and/or renin based on the analysis of stored urine biosamples from subjects with type 1 diabetes in the DCCT study who were followed longitudinally for 9 years.