The Role of Nrf2 in Proteinuric Chronic Kidney Disease

Nrf2 在蛋白尿性慢性肾病中的作用

• 批准号: 10363868
• 负责人: Roderick Jason Tan
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363868
• 关键词: Adriamycin PFS; Affect; Albuminuria; American; Angiotensin II; Animal Model; Animals; Antioxidants; Basement membrane; Biological Models; Biology; Cardiovascular Diseases; Cell Nucleus; Cells; Cellular Stress; Chronic; Chronic Kidney Failure; Clinic; Clinical Trials; Consumption; Data; Diabetes Mellitus; Diabetic Nephropathy; Dialysis procedure; Disease; Disease Progression; Dose; Drug Metabolic Detoxication; End stage renal failure; Endothelial Cells; Endothelium; Enhancers; Etiology; Excretory function; Experimental Models; Exposure to; Fibrosis; Focal Segmental Glomerulosclerosis; Foot Process; Functional disorder; General Population; Genes; Genetic; Glomerular Filtration Rate; Goals; Health; Health Care Costs; Hereditary nephritis; High Prevalence; Human; Individual; Injury; Injury to Kidney; Kidney; Kidney Failure; Kidney Transplantation; Knock-out; Knockout Mice; Lead; Malignant Neoplasms; Mediator of activation protein; Modeling; Mus; Nuclear Translocation; Pathologic; Pathway interactions; Patients; Pharmacology; Play; Population; Prevalence; Proteins; Proteinuria; Reactive Oxygen Species; Renal dialysis; Renal glomerular disease; Risk; Role; Testing; Therapeutic; Time; Tubular formation; United States Department of Veterans Affairs; Up-Regulation; Urine; Veterans; Wild Type Mouse; Work; adverse outcome; analog; cell type; clinically relevant; conditional knockout; effective therapy; glomerular filtration; glomerulosclerosis; human disease; improved; inhibitor; interstitial; kidney cell; military veteran; mouse model; nuclear factor-erythroid 2; podocyte; preclinical study; transcription factor; transcriptome sequencing; trigonelline; urinary

Chronic kidney disease (CKD) affects over 35 million Americans, and veterans have a higher prevalence of CKD compared to the general population. Progressive CKD leads to end-stage renal disease (ESRD), a state of complete kidney failure requiring dialysis or renal transplantation for survival. Glomerular diseases are the leading cause of CKD and are caused by diseases such as diabetic nephropathy, Alport syndrome, and focal segmental glomerulosclerosis. All of these diseases are characterized by abnormal urinary protein excretion (proteinuria). This is caused by the dysfunction of the glomerular filtration barrier which is comprised of endothelial cells, podocytes, and their shared basement membrane. Treatments for proteinuric CKD are extremely limited, with most slowing progression of disease rather than curing it. Thus, the unmet need for proteinuric CKD is to improve therapeutics through a better understanding of glomerular biology. Nuclear factor erythroid 2 related 2 (Nrf2) is a transcription factor that upregulates cytoprotective antioxidant and detoxification genes. Although primed to activate quickly during cellular stress, it is restrained by its inhibitor Kelch- like ECH-associated protein 1 (Keap1) under normal conditions. Nrf2 can be pharmacologically activated with compounds such as bardoxolone methyl (CDDO-Me) and its analog CDDO-Im. Recently completed and ongoing human clinical trials utilize bardoxolone methyl to treat proteinuric CKD. These trials have consistently demonstrated an increase in glomerular filtration rates (eGFR), but whether this effect leads to an overall benefit in patients is controversial. Furthermore, bardoxolone methyl caused a worsening of proteinuria in diabetic kidney disease, but not in Alport syndrome. In our preliminary work, we find that genetic and pharmacologic Nrf2 enhancement worsened podocyte injury and proteinuria in several experimental models of CKD in mice. Our proposal will focus on the pros and cons of Nrf2 in proteinuric CKD to better understand its role in disease. In Specific Aim 1, we will examine whether Nrf2 plays differential roles in diabetic kidney disease and Alport syndrome. In Specific Aim 2, we will test the effects of Nrf2 in different kidney cells using conditional knockout mice. In Specific Aim 3, we will evaluate how dose or timing of Nrf2 affects the overall course of disease. Surprisingly, there are few preclinical studies to support the use of Nrf2 enhancers in CKD. A systematic and comprehensive assessment of Nrf2 in animal models is required to guide the rational use of Nrf2 enhancers in the clinic. Our proposal will provide this critical data with the goal of improving the lives of our veterans and of all patients with CKD.

慢性肾病 (CKD) 影响着超过 3500 万美国人，退伍军人的患病率更高 与一般人群相比，CKD 患病率。进行性 CKD 导致终末期 肾病（ESRD），一种需要透析或肾功能衰竭的完全肾衰竭状态 移植以求生存。肾小球疾病是 CKD 的主要原因 糖尿病肾病、阿尔波特综合征、局灶性节段性肾病等疾病 肾小球硬化。所有这些疾病的特征都是尿蛋白异常 排泄（蛋白尿）。这是由于肾小球滤过屏障功能障碍引起的 它由内皮细胞、足细胞及其共享的基底膜组成。 蛋白尿性 CKD 的治疗方法极其有限，大多数可以减缓疾病进展 而不是治愈它。因此，蛋白尿 CKD 未满足的需求是改进治疗方法 通过更好地了解肾小球生物学。核因子红细胞2相关2 (Nrf2) 是一种上调细胞保护性抗氧化剂和解毒基因的转录因子。 尽管在细胞应激期间会快速激活，但它受到其抑制剂 Kelch-的抑制 就像正常条件下的 ECH 相关蛋白 1 (Keap1) 一样。 Nrf2可以在药理学上 用巴多索隆甲基 (CDDO-Me) 及其类似物 CDDO-Im 等化合物激活。 最近完成和正在进行的人体临床试验利用甲基巴多索隆来治疗 蛋白尿慢性肾病。这些试验一致证明肾小球 滤过率（eGFR），但这种效应是否会给患者带来总体益处尚不清楚 有争议的。此外，甲基巴多索龙会导致糖尿病患者蛋白尿恶化。 肾脏疾病，但不是阿尔波特综合征。在我们的初步工作中，我们发现遗传和 药理 Nrf2 增强会加重一些患者的足细胞损伤和蛋白尿 小鼠 CKD 实验模型。我们的建议将重点关注 Nrf2 在以下方面的优缺点： 蛋白尿 CKD 以更好地了解其在疾病中的作用。在具体目标 1 中，我们将研究 Nrf2 是否在糖尿病肾病和 Alport 综合征中发挥不同作用。具体来说 目标2，我们将使用条件敲除小鼠测试Nrf2在不同肾细胞中的作用。 在具体目标 3 中，我们将评估 Nrf2 的剂量或时间如何影响整个疗程 疾病。令人惊讶的是，很少有临床前研究支持 Nrf2 增强剂在 慢性肾病。需要对动物模型中的 Nrf2 进行系统和全面的评估 指导临床合理使用Nrf2增强剂。我们的提案将提供这些关键数据 我们的目标是改善退伍军人和所有 CKD 患者的生活。