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.

慢性肾脏疾病（CKD）影响超过3500万美国人，而退伍军人则更高 与普通人群相比，CKD的患病率。渐进的CKD导致终点 肾脏疾病（ESRD），这是一种完全肾衰竭的状态，需要透析或肾脏 移植以生存。肾小球疾病是CKD的主要原因，是引起的 通过糖尿病性肾病，ALPORP综合征和局灶性分段等疾病 肾小球硬化。所有这些疾病的特征是异常尿蛋白 排泄（蛋白尿）。这是由于肾小球滤过屏障的功能障碍引起的 由内皮细胞，足细胞及其共用地下膜组成。 蛋白尿CKD的治疗极为有限，疾病进展大多 而不是治愈它。 Thus, the unmet need for proteinuric CKD is to improve therapeutics 通过更好地了解肾小球生物学。核因子红系2相关2（NRF2） 是上调细胞保护抗氧化剂和解毒基因的转录因子。 尽管在细胞应激期间迅速激活，但它受到其抑制剂kelch-的限制 像在正常条件下与ECH相关的蛋白1（KEAP1）。 NRF2可以是药理 用诸如Bardoxolone甲基（CDDO-ME）及其模拟CDDO-IM等化合物激活。 最近完成和正在进行的人类临床试验利用bardoxolone甲基治疗 蛋白尿CKD。这些试验始终显示出肾小球的增加 过滤率（EGFR），但是这种影响是否导致患者的总体好处是 有争议的。此外，bardoxolone甲基在糖尿病患者中导致蛋白尿恶化 肾脏疾病，但不在Alport综合征中。在我们的初步工作中，我们发现了遗传和 药理学NRF2增强在几个 小鼠CKD的实验模型。我们的建议将重点介绍NRF2的利弊 蛋白尿CKD可以更好地了解其在疾病中的作用。在特定目标1中，我们将检查 NRF2是否在糖尿病肾脏疾病和Alport综合征中起鉴别作用。具体 AIM 2，我们将使用条件基因敲除小鼠测试NRF2在不同肾细胞中的影响。 在特定目标3中，我们将评估NRF2的剂量或时间如何影响 疾病。令人惊讶的是，很少有临床前研究可以支持NRF2增强剂的使用 CKD。需要在动物模型中对NRF2进行系统的全面评估 指导NRF2增强子在诊所中的合理使用。我们的建议将提供这些关键数据 目的是改善退伍军人和所有CKD患者的生活。