Mechanisms of iron-mediated renal injury in lupus nephritis

狼疮性肾炎铁介导的肾损伤机制

基本信息

批准号：
10337330
负责人：
Erika Ingrid Boesen
金额：
$ 33.72万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-09 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10337330
关键词：
Acute Adrenal Cortex Hormones Affect Age Albuminuria American Antioxidants Attenuated Autoimmune Diseases Biological Markers Black race Body part Cell Culture Techniques Cell Death Cells Cessation of life Chronic Chronic Kidney Failure Clinical Research Coenzyme A Ligases Complement Complementary therapies Complication Data Diagnosis Disease Disease remission Drug Targeting Enzymes Excretory function Exposure to FDA approved Family member Fibrosis Filtration Genetic Goals Homeostasis Immune system Immunosuppression Impairment In Transferrin Inflammation Injury Injury to Kidney Iron Iron Chelating Agents Kidney Link Literature Lupus Lupus Nephritis Mediating Mediator of activation protein Modeling Mus NZW Mouse Nephrons New Zealand Organ Oxidative Stress Pathway interactions Patients Permeability Pharmaceutical Preparations Process Proteinuria Publishing Renal tubule structure Reporting Risk Role Scheme Signal Transduction Source Stimulus Systemic Lupus Erythematosus Testing Transferrin Tubular formation Up-Regulation Urine Work antioxidant enzyme base cell injury cell type child bearing experimental study genetic approach glutathione peroxidase in vivo inhibitor insight iron metabolism kidney cell kidney dysfunction mouse model novel novel strategies novel therapeutic intervention patient biomarkers patient prognosis podocyte premature protein metabolism renal damage side effect systemic autoimmune disease targeted agent treatment strategy uptake urinary young woman

项目摘要

PROJECT SUMMARY/ABSTRACT Lupus is a chronic, often debilitating autoimmune disease that predominantly affects young women. Damage to the kidneys (lupus nephritis) is a serious and common complication of lupus, affecting approximately 50% of patients, and has been linked with poor patient prognosis and increased risk of premature death. Current treatments for lupus are based on suppressing the immune system and inflammation. Unfortunately, these treatments, which include corticosteroids, have serious side effects and in many patients do not adequately protect the kidneys, highlighting the need for new treatment approaches. Iron is an important component of the body, but when present in excess can cause damage to cells. Evidence suggests that iron metabolism may be abnormal in the kidneys of lupus patients, with a growing body of literature indicating that several iron metabolism proteins can serve as urinary biomarkers of lupus nephritis. Our published report demonstrates that iron accumulation is increased in the kidneys and that reducing body iron levels helps to protect the kidneys from developing injury in a mouse model of lupus nephritis. This proposal investigates the mechanisms by which iron promotes kidney injury in lupus, with our goal being to specifically block these damaging effects while maintaining normal iron homeostasis. Specifically, we propose that in lupus nephritis, enhanced filtration of iron sources, including transferrin, leads to glomerular and tubular injury including iron- induced cell death (ferroptosis), contributing to the progression of kidney injury in lupus nephritis. Ferroptosis is a recently described form of cell death and has never been studied or targeted in lupus. Our preliminary data show that one of the key mediators of ferroptosis, the enzyme acyl-CoA synthetase long chain family member 4 (ACSL4), is dramatically upregulated in glomeruli and renal tubules around the onset of albuminuria in mice with lupus, with further increases evident as injury progresses. We will conduct experiments in genetic and inducible mouse models of lupus nephritis to test the role of iron and ACSL4 in promoting both glomerular and tubular injury in lupus nephritis, and whether drugs targeting iron accumulation or players in the ferroptotic pathway can stop further progression of renal injury. Together, these experiments will provide important novel insights into the disease mechanisms underlying the progression of renal injury in lupus, and offer potential new therapeutic approaches to treating lupus nephritis.

项目概要/摘要狼疮是一种慢性、常常使人衰弱的自身免疫性疾病，主要影响年轻女性。损坏肾脏（狼疮性肾炎）是狼疮的一种严重且常见的并发症，影响约 50% 患者，并与患者预后不良和过早死亡风险增加有关。当前的狼疮的治疗基于抑制免疫系统和炎症。不幸的是，这些包括皮质类固醇在内的治疗具有严重的副作用，并且在许多患者中没有充分发挥作用保护肾脏，强调需要新的治疗方法。铁是人体的重要组成部分但过量时会对细胞造成损害。有证据表明铁代谢可能狼疮患者的肾脏异常，越来越多的文献表明，几种铁代谢蛋白可以作为狼疮性肾炎的尿液生物标志物。我们发布的报告表明肾脏中的铁积累增加，降低体内铁水平有助于保护狼疮性肾炎小鼠模型中肾脏受到损伤。该提案调查了铁促进狼疮肾损伤的机制，我们的目标是专门阻止这些机制破坏性影响，同时维持正常的铁稳态。具体来说，我们建议在狼疮性肾炎中，铁源（包括转铁蛋白）的过滤增强会导致肾小球和肾小管损伤，包括铁- 诱导细胞死亡（铁死亡），导致狼疮性肾炎肾损伤的进展。铁死亡是最近描述的一种细胞死亡形式，从未在狼疮中进行过研究或针对。我们的初步数据表明铁死亡的关键介质之一，酰基辅酶A合成酶长链家族成员 4 (ACSL4)，在小鼠白蛋白尿发作前后在肾小球和肾小管中显着上调对于狼疮，随着损伤的进展，其进一步明显增加。我们将进行遗传和实验诱导狼疮性肾炎小鼠模型，以测试铁和 ACSL4 在促进肾小球和肾小球肾功能中的作用狼疮性肾炎中的肾小管损伤，以及针对铁积累或铁死亡中的参与者的药物是否途径可以阻止肾损伤的进一步进展。总之，这些实验将提供重要的新颖性深入了解狼疮肾损伤进展的疾病机制，并提供潜在的帮助治疗狼疮性肾炎的新治疗方法。