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

• 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
• 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

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.

摘要 糖尿病肾病是糖尿病的一种严重的微血管并发症，是导致终末期糖尿病的主要原因。 肾脏疾病的阶段。多项研究表明，炎症在糖尿病的发病机制中起着关键作用。 糖尿病肾病的发病机制。这种炎症反应会损害肾实质，并 促进有缺陷的钠处理，最终容易患高血压。虽然很强大 有证据支持这些观察，即钠滞留增加背后的分子机制 糖尿病肾单位的病因尚不清楚。研究表明，血管紧张素转换酶 血管紧张素转换酶(ACE)是肾炎进展的主要参与者。尽管血管紧张素转换酶的大部分作用 血管紧张素转换酶与血管紧张素II的合成经典相关，最近的研究强调了血管紧张素转换酶在炎症中的作用 以及通过独立于血管紧张素II产生的机制进行免疫反应。的确， 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 除血管紧张素外，还有多种底物。I.初步数据显示，肾小管上皮细胞 产生白介素1β(IL-1β)以响应高糖通过一种需要 功能性血管紧张素转换酶N结构域，不依赖于血管紧张素II的合成。这种细胞因子调节 肾钠转运蛋白的活性。此外，体内研究表明，糖尿病小鼠缺乏功能性 ACE N结构域显示出较低的肾脏IL-1β水平，并改善了钠的处理能力 2型糖尿病小鼠。根据这些数据，我推测，在糖尿病期间，ACE调节释放 肾小管上皮细胞产生IL-1β的非血管紧张素II机制 一代。IL-1β进一步促进炎症反应和钠处理受损 与糖尿病肾病有关。为了探索这一点，我提出了三个具体目标：1)调查 血管紧张素转换酶C区和N区在肾上皮细胞产生IL-1β中的特异性作用 确定该细胞因子是如何在体外调节肾脏钠转运蛋白活性的。2)确定 血管紧张素转换酶C和N结构域在肾损伤和肾损害中的作用机制 体内钠处理受损与糖尿病肾病相关。3)为了研究源头， 细胞靶点及IL-1β在肾损伤和钠处理受损中的作用 糖尿病肾病。总而言之，这项提议表明了一种新的生化通讯方式 肾单位的不同部分，上皮细胞产生的细胞因子可以改变钠离子 沿肾单位的亲和力。这些研究可能会带来治疗糖尿病的新方法。 治疗肾病，防止发展为严重的临床疾病，如终末期肾病。