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（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。这一观点基于间接证据和 RAS 阻滞剂已知的治疗益处。我们假设 1 型糖尿病患者尿液中血管紧张素原 (AOG) 和肾素的增加将提供肾脏 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 型糖尿病受试者进行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 研究参与者的尿液样本中的 AOG 和肾素，这些参与者在 9 年纵向随访期间未接受 RAS 阻滞剂或任何其他抗高血压药物治疗。我们将研究以下问题：是否可以通过尿 AOG 和肾素水平来预测微量白蛋白尿和大量白蛋白尿范围内白蛋白尿的发生。此外，我们计划测量总 AOG 以及活跃（完整）AOG。为了测量完整的 AOG，将使用一种新型 ELISA 测定法。完整（或活性）AOG 反映了通过肾素裂解形成 Ang I 的潜力，比目前测定法测得的总 AOG 更好，并且该过程中消耗的 AOG 量可以从完整 AOG 与总 AOG 的比率推断出来。尿肾素的调节似乎与血浆肾素不同，并且在糖尿病中会增加。因此，与糖尿病患者血浆肾素活性降低不同，尿肾素活性可能升高，反映出肾脏 RAS 过度活跃。最近发现了肾脏中的旁分泌信号通路，通过该通路高水平的葡萄糖触发肾素的释放。我们假设，与传统胰岛素治疗组相比，DCCT 参与者强化胰岛素治疗所提供的代谢控制的改善对肾脏 RAS 产生更有效的下调作用，这将通过尿 AOG 和肾素水平降低来体现。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的分析，确定正常白蛋白尿、微量白蛋白尿和大量白蛋白尿的 1 型糖尿病的尿液 RAS 谱（AOG 和肾素）。目标 2. 根据纵向跟踪 9 年的 DCCT 研究中对 1 型糖尿病受试者储存的生物样本进行分析，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生。目标 3. 基于对 DCCT 研究中 1 型糖尿病受试者储存的尿液生物样本进行分析（纵向随访 9 年），确定正常白蛋白尿、微量白蛋白尿和大量白蛋白尿受试者中强化胰岛素治疗所提供的血糖控制改善是否会降低尿 AOG 和/或肾素。