The role of angiotensin-converting enzyme in renal inflammation, kidney injury and sodium retention during diabetic nephropathy

血管紧张素转换酶在糖尿病肾病肾脏炎症、肾损伤和钠潴留中的作用

基本信息

批准号：
10188616
负责人：
KENNETH E BERNSTEIN
金额：
$ 42.5万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188616
关键词：
Affect Albuminuria Angiotensin I Angiotensin II Angiotensin-Converting Enzyme Inhibitors Animal Model Anti-Inflammatory Agents Applications Grants Avidity Biochemical Cells Clinical Communication Data Development Diabetes Mellitus Diabetic Angiopathies Diabetic Nephropathy Diabetic mouse Distal End stage renal failure Epithelial Cells Excretory function Generations Glucose Grant Hypertension Immune response Impairment In Vitro Inflammation Inflammatory Inflammatory Response Injury to Kidney Interleukin-1 beta Kidney Lead Liquid substance Modernization Molecular N Domain Nephrons Oligopeptides Pathogenesis Pathology Peptidyl-Dipeptidase A Phenotype Play Process Production Regulation Renal function Renin-Angiotensin System Research Role Sodium Source System Tubular formation Up-Regulation base cellular targeting cytokine diabetic diabetic patient enzyme activity epithelial Na+ channel improved in vitro activity in vivo nephrogenesis novel novel therapeutic intervention prevent renal epithelium response type I diabetic urinary

项目摘要

ABSTRACT Diabetic nephropathy is a serious microvascular complication of diabetes and the main cause of end- stage renal disease. Several studies have demonstrated a critical role of inflammation in the pathogenesis of diabetic kidney disease. This inflammatory response injures the renal parenchyma and promotes a defective sodium handling that, ultimately, predispose to hypertension. Although strong evidence supports these observations, the molecular mechanisms behind the increased sodium retention of the diabetic nephron remain unknown. Research demonstrates that angiotensin-converting enzyme (ACE) is a major player in the progression of renal inflammation. Although most effects of ACE have been classically related to angiotensin II synthesis, recent studies highlight a role of ACE in inflammation and immune response through mechanisms that are independent of angiotensin II production. Indeed, ACE has two catalytically independent domains, known as the N- and C-domains, that can process a wide diversity of substrates besides angiotensin I. Preliminary data show that renal tubular epithelial cells produce interleukin-1β (IL-1β) in response to high glucose through a mechanism that requires a functional ACE N-domain and is independent of angiotensin II synthesis. This cytokine regulates the activity of renal sodium transporters. Also, in vivo studies show that diabetic mice lacking a functional ACE N-domain display lower levels of renal IL-1β and have improved sodium handling compared to wild- type diabetic mice. Based on these data, I hypothesize that, during diabetes, ACE regulates the release of IL-1β from renal tubular epithelial cells through a mechanism that is independent from angiotensin II generation. IL-1β further contributes to the inflammatory response and the impaired sodium handling associated with diabetic nephropathy. To explore this, I propose three specific aims: 1) To investigate the specific contribution of the ACE C- and N-domains to the production of IL-1β by renal epithelial cells and determine how this cytokine regulates renal sodium transporter activity in vitro. 2) To determine the mechanism by which the ACE C- and N-domains contribute to the development of kidney injury and impaired sodium handling associated with diabetic nephropathy in vivo. 3) To study the source, the cellular target and the role of IL-1β in kidney injury and impaired sodium handling associated with diabetic nephropathy. In conclusion, this proposal suggests a novel biochemical communication between different portions of the nephron where cytokines produced by epithelial cells can modify the sodium avidity along the nephron. These studies might lead to new therapeutic approaches to treat diabetic nephropathy and prevent the development of serious clinical conditions such as end-stage renal disease.

抽象的糖尿病肾病是糖尿病严重的微血管并发症，是导致糖尿病终末期死亡的主要原因。多项研究表明炎症在肾病阶段发挥着关键作用。这种炎症反应会损伤肾实质并导致糖尿病肾病的发病机制。促进钠处理缺陷，最终导致高血压。证据支持这些观察结果，即钠潴留增加背后的分子机制研究表明，血管紧张素转换酶对糖尿病肾单位的作用尚不清楚。 (ACE) 是肾脏炎症进展的主要参与者，尽管 ACE 的大部分作用具有以下作用。传统上与血管紧张素 II 合成相关，最近的研究强调了 ACE 在炎症中的作用事实上，通过独立于血管紧张素 II 产生的机制进行免疫反应。 ACE 有两个催化独立的结构域，称为 N 结构域和 C 结构域，可以处理除血管紧张素 I 外，底物具有广泛的多样性。初步数据表明，肾小管上皮细胞通过一种机制产生白细胞介素-1β (IL-1β) 以响应高葡萄糖，该机制需要功能性 ACE N 结构域，不依赖于血管紧张素 II 的合成。此外，体内研究表明糖尿病小鼠缺乏功能性钠转运蛋白。与野生型相比，ACE N 结构域显示出较低水平的肾 IL-1β，并改善了钠处理能力。根据这些数据，我发现在糖尿病期间，ACE 会调节释放。通过独立于血管紧张素 II 的机制从肾小管上皮细胞中产生 IL-1β IL-1β的产生进一步促进炎症反应和钠处理受损。为了探索这一点，我提出了三个具体目标：1）研究 ACE C 和 N 结构域对肾上皮细胞产生 IL-1β 的具体贡献确定该细胞因子如何在体外调节肾钠转运蛋白活性 2) 确定 ACE C 和 N 结构域促进肾损伤发展的机制体内钠处理与糖尿病肾病相关 3) 研究来源。细胞靶标以及 IL-1β 在肾损伤和钠处理受损中的作用总之，该提议提出了糖尿病肾病之间的一种新的生化通讯。肾单位的不同部分，上皮细胞产生的细胞因子可以改变钠这些研究可能会带来治疗糖尿病的新方法。肾病并预防严重临床疾病的发展，例如终末期肾病。