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.

项目摘要/摘要狼疮是一种慢性，经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（狼疮肾炎）是狼疮的严重且常见的并发症，约有50％患者，与患者预后不良和过早死亡的风险增加有关。当前的狼疮的治疗方法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疗法具有严重的副作用，在许多患者中保护肾脏，强调对新治疗方法的需求。铁是身体，但是当出现过量时会对细胞造成损害。证据表明铁代谢可能是狼疮患者的肾脏异常，文献越来越多，表明几种铁代谢蛋白可以用作狼疮肾炎的尿生物标志物。我们发表的报告证明了肾脏中铁的积累增加了，降低的人体铁水平有助于保护狼疮肾炎的小鼠模型中出现损伤的肾脏。该提案调查了铁在狼疮中促进肾脏损伤的机制，我们的目标是专门阻止这些在维持正常铁稳态的同时，有害影响。具体而言，我们建议在狼疮肾炎中，铁源的过滤增强，包括转铁蛋白，导致肾小球和管状损伤，包括铁诱导的细胞死亡（铁凋亡），导致狼疮肾炎中肾脏损伤的进展。铁凋亡是最近描述的细胞死亡形式，从未在狼疮中进行研究或靶向。我们的初步数据表明酶酰基辅酶A合成酶长链家族成员是铁凋亡的关键介体之一 4（ACSL4）在小鼠蛋白尿发作周围的肾小球和肾小管中急剧上调随着狼疮的进一步增加，随着伤害的进一步发展。我们将在遗传和狼疮肾炎的诱导小鼠模型测试铁和ACSL4在促进肾小球和狼疮性肾炎中的管状损伤，以及靶向铁积累的药物还是螺旋菌中的参与者途径可以停止进一步的肾脏损伤进展。这些实验将共同提供重要的小说洞悉狼疮中肾脏损伤进展的疾病机制，并提供潜力治疗狼疮肾炎的新治疗方法。