Urinary Renin Angiotensin System in Diabetes

糖尿病中的尿肾素血管紧张素系统

• 批准号: 8964763
• 负责人: DANIEL BATLLE
• 金额: $ 34.76万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8964763
• 关键词: Albuminuria; Angiotensinogen; Animals; Antihypertensive Agents; Biological Assay; Chronic Kidney Failure; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Enrollment; Enzyme-Linked Immunosorbent Assay; Exclusion; Gene Expression; Glomerular Filtration Rate; Glucose; Human; Hyperglycemia; Hypertension; Insulin; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Measurement; Measures; Metabolic; Metabolic Control; Microalbuminuria; Paracrine Communication; Participant; Patients; Pharmaceutical Preparations; Phase; Physiological; Plasma; Process; Renin; Renin-Angiotensin System; Reporting; Rodent Model; Sampling; Signal Pathway; System; Testing; Therapeutic; Urine; arm; base; cohort; conventional therapy; diabetes control; diabetic; follow-up; glycemic control; improved; insight; macroalbuminuria; novel; prevent; public health relevance; urinary

 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.

 描述（通过应用提供）：肾脏肾素 - 血管紧张素系统（RAS）的激活有助于糖尿病性肾病的发展。该概念基于间接证据和RAS阻滞剂的已知治疗益处。我们假设从患有1型糖尿病的受试者的尿液中增加的血管紧张素原（AOG）和肾素会提供肾脏RAS激活的早期特征。参加糖尿病控制和并发症试验（DCCT）的1型糖尿病的受试者的纵向随访为检验该假设提供了独特的机会。我们建议在DCCT研究的参与者的尿液样本中评估AOG和肾素，他们在9年的纵向随访中未接受RAS阻滞剂或任何其他抗高血压药物的治疗。我们将研究一个问题，即在微珠尿和大藻次范围内的蛋白尿的发展是否可以通过尿尿和肾素的水平来预测。此外，我们计划测量总AOG以及主动（完整）AOG。为了测量完整的AOG，将使用新型ELISA分析。完整的（或活跃）AOG反映了通过当前测定法测量的肾素裂解比总AOG更好地形成ANG I的潜力，并且可以从完整的AOG与总AOG的比例中推断出该过程中消耗的AOG量。尿素肾素似乎与血浆中的肾素不同，并且在糖尿病中增加。与糖尿病中增加的血浆肾素活性不同，尿素可能会增加并反映出过度活跃的肾脏RA。最近已经确定了肾脏中的旁分泌信号通路，从而高水平的葡萄糖会触发肾素的释放。我们假设，与常规的胰岛素治疗臂相比，DCCT参与者的强化胰岛素治疗对DCCT参与者的强化胰岛素治疗提供了更有效的下调节作用，这将表现出对肾脏RAS的更有效的下调作用，并且这将通过尿液AOG和肾素的降低表现出来。具体目的是：目标1。基于DCCT研究中有1型糖尿病的受试者的储存尿液生物样品的分析，定义具有正常珠尿症，微珠尿症和大藻蛋白尿的1型糖尿病的尿液RAS谱（AOG和肾素）。目的2。确定尿血管紧张素原和/或肾素是否会增加基于对DCCT研究中1型糖尿病患者的储存生物样本的分析，是否会纵向持续9年。目的3。确定在胰岛素尿症的受试者中通过强化胰岛素治疗提供的改善血糖控制，微珠蛋白尿，微珠尿症和大藻尿症是否基于对1型dcct研究中1型Diabetes的受试者储存的尿液生物样本的分析，从而降低了尿液和/或肾素的尿素和/或肾素。