Urinary Renin Angiotensin System in Diabetes

 描述（由申请方提供）：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生。这一观点基于间接证据和RAS阻滞剂的已知治疗获益。我们假设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激活的早期特征。对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独特的机会。我们建议同时评估DCCT研究中未接受RAS阻断剂或任何其他降压药物治疗的受试者在9年纵向随访期间的尿液样本中的AOG和肾素。我们将研究尿AOG和肾素水平是否可以预测微量白蛋白尿和大量白蛋白尿范围内的白蛋白尿的发生。此外，我们计划测量总AOG以及活动（完整）AOG。对于完整AOG的测量，将使用新的ELISA测定。完整的（或活性的）AOG比总AOG更好地反映了通过肾素切割形成Ang I的潜力，如通过当前测定所测量的，并且在该过程中消耗的AOG的量可以从完整的AOG与总AOG的比率推断。尿肾素的调节似乎与血浆中的肾素不同，并且在糖尿病中增加。因此，与糖尿病患者血浆肾素活性降低不同，尿肾素可能升高，反映肾脏RAS过度活跃。最近已经确定了肾脏中的旁分泌信号通路，由此高水平的葡萄糖触发肾素的释放。我们假设DCCT受试者强化胰岛素治疗改善代谢控制，与常规胰岛素治疗组相比，对肾脏RAS产生更有效的下调作用，这将通过降低尿AOG和肾素水平来证明。具体目标是：目标1。根据DCCT研究中1型糖尿病受试者储存的尿液生物样本分析，确定1型糖尿病伴正常白蛋白尿、微量白蛋白尿和大量白蛋白尿的尿液RAS特征（AOG和肾素）。目标2.根据DCCT研究中1型糖尿病受试者储存的生物样本分析，确定尿血管紧张素原和/或肾素升高是否先于微量白蛋白尿和大量白蛋白尿的发生，纵向随访9年。目标3：根据DCCT研究中1型糖尿病受试者（纵向随访9年）的储存尿液生物样本分析，确定强化胰岛素治疗在正常白蛋白尿、微量白蛋白尿和大量白蛋白尿受试者中提供的血糖控制改善是否会降低尿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.