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.

抽象的糖尿病性肾病是糖尿病的严重微血管并发症，是末期的主要原因阶段肾脏疾病。几项研究表明，炎症在糖尿病肾脏疾病的发病机理。这种炎症反应损伤肾实质和促进钠处理有缺陷的处理，最终使高血压易于高血压。虽然很强证据支持这些观察结果，即钠保留率增加背后的分子机制糖尿病性肾单位的含量仍然未知。研究表明，血管紧张素转化酶（ACE）是肾脏注射进展的主要参与者。虽然王牌的大多数影响与血管紧张素II合成相关，最近的研究突出了ACE在炎症中的作用通过与血管紧张素II产生无关的机制和免疫响应。的确， ACE具有两个催化独立的域，称为N-和C域，可以处理A 除血管紧张素外，底物的多样性I.初步数据表明肾小管上皮细胞通过需要一种机制，生产白介素-1β（IL-1β），以对高葡萄糖进行响应功能性ACE N-域，与血管紧张素II合成无关。这种细胞因子调节肾脏钠转运蛋白的活性。此外，体内研究表明，缺乏功能性的糖尿病小鼠 ACE N域显示较低水平的肾脏IL-1β，与野生 - 型糖尿病小鼠。基于这些数据，我假设在糖尿病期间，ACE调节释放通过独立于血管紧张素II的机制，来自肾小管上皮细胞的IL-1β 一代。 IL-1β进一步有助于炎症反应和钠处理受损与糖尿病性肾病有关。为了探讨这一点，我提出了三个具体目标：1）调查 ACE C和N-域对肾上皮细胞和IL-1β产生的特定贡献确定该细胞因子如何在体外调节肾脏钠转运蛋白活性。 2）确定 ACE C和N域有助于肾脏损伤的发展的机制与糖尿病性肾病相关的钠处理受损。 3）研究来源，细胞靶和IL-1β在肾脏损伤中的作用以及与糖尿病性肾病。总之，该提议提出了一种新颖的生化交流肾单位的不同部分，上皮细胞产生的细胞因子可以改变钠沿着肾单位的亲和力。这些研究可能导致新的治疗糖尿病治疗方法肾病并防止严重的临床状况（例如终末期肾脏疾病）的发展。