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.

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。 阶段肾病。多项研究表明炎症在 糖尿病肾病的发病机制。这种炎症反应会损伤肾实质 促进钠处理缺陷，最终导致高血压。虽然很强 证据支持这些观察结果，即钠潴留增加背后的分子机制 糖尿病肾单位的作用仍不清楚。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。尽管 ACE 的大部分作用 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 以及通过独立于血管紧张素 II 产生的机制产生的免疫反应。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 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。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 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。 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 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 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。为了探索这个问题，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-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 体内钠处理受损与糖尿病肾病相关。 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 糖尿病肾病。总之，该提案提出了一种新颖的生化通讯 肾单位的不同部分，上皮细胞产生的细胞因子可以改变钠 沿着肾单位的亲和力。这些研究可能会带来治疗糖尿病的新方法 肾病并预防严重临床疾病的发展，例如终末期肾病。