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严重的微血管并发症，是糖尿病终末期肾病的主要原因。 肾病分期几项研究已经证明了炎症在炎症中的关键作用。 糖尿病肾病的发病机制。这种炎症反应损伤肾实质， 促进钠处理缺陷，最终导致高血压。尽管强 证据支持这些观察结果，增加钠潴留背后的分子机制 糖尿病肾单位的分布仍不清楚。研究表明血管紧张素转换酶 (ACE)是肾脏炎症进展的主要参与者。虽然ACE的大多数作用 ACE与血管紧张素II的合成密切相关，最近的研究强调了ACE在炎症中的作用 和免疫反应的机制是独立的血管紧张素II的生产。的确， ACE具有两个催化独立的结构域，称为N-和C-结构域，其可以处理 除了血管紧张素I之外，还有多种底物。初步数据显示肾小管上皮细胞 产生白细胞介素-1 β（IL-1 β），通过一种机制， 功能性ACE N-结构域，并且独立于血管紧张素II的合成。这种细胞因子调节 肾钠转运体的活性。此外，体内研究表明，糖尿病小鼠缺乏功能性 与野生型相比，ACE N结构域显示肾脏IL-1 β水平较低，并改善了钠处理。 型糖尿病小鼠基于这些数据，我假设，在糖尿病期间，ACE调节 通过不依赖于血管紧张素II的机制从肾小管上皮细胞中释放IL-1 β 一代IL-1 β进一步促进炎症反应和受损的钠处理 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 ACE C-和N-结构域对肾上皮细胞产生IL-1 β的特异性贡献， 确定这种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， 与体内糖尿病肾病相关的钠处理受损。3)为了研究其来源， 细胞靶点和IL-1 β在肾损伤中的作用以及与糖尿病相关的钠处理受损 糖尿病肾病总之，这一建议表明，一种新的生化通讯之间 肾单位的不同部分，其中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。这些研究可能会导致新的治疗方法来治疗糖尿病 肾病和预防严重的临床病症如终末期肾病的发展。