Mechanisms of iron-mediated renal injury in lupus nephritis

狼疮性肾炎铁介导的肾损伤机制

• 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
• 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

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 狼疮是一种慢性的、经常使人虚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)是狼疮的一种严重和常见的并发症，影响大约50%的 并与患者预后不良和过早死亡风险增加有关。当前 狼疮的治疗是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有严重的副作用，在许多患者中没有得到充分的治疗。 保护肾脏，强调需要新的治疗方法。铁是人体健康的重要组成部分 但过量存在时会对细胞造成损害。有证据表明，铁的代谢可能是 狼疮患者肾脏异常，越来越多的文献表明几种铁 代谢蛋白可作为狼疮性肾炎的尿生物标志物。我们发布的报告表明 肾脏中铁的积累增加，降低体内的铁水平有助于保护 狼疮性肾炎小鼠模型的肾脏损伤。这项提案调查了 铁促进狼疮肾损伤的机制，我们的目标是专门阻止这些 在维持正常铁平衡的同时产生破坏性影响。具体地说，我们建议在狼疮性肾炎中， 加强铁源的过滤，包括转铁蛋白，导致肾小球和肾小管损伤，包括铁- 诱导细胞死亡(铁性下垂)，促进狼疮性肾炎肾损伤的进展。铁性上睑下垂 一种最近被描述的细胞死亡形式，从未在狼疮中被研究或靶向。我们的初步数据 研究表明，铁下垂的关键介质之一，酰基辅酶A合成酶长链家族成员 4(ACSL4)在蛋白尿小鼠的肾小球和肾小管中显著上调 对于狼疮，随着损伤的进展，进一步的增加是明显的。我们将进行基因和基因方面的实验 诱导狼疮性肾炎小鼠模型研究铁和ACSL4对肾小球和肾小球功能的影响 狼疮性肾炎中的肾小管损伤，以及针对铁蓄积的药物还是铁上皮症患者的药物 途径可以阻止肾损伤的进一步发展。总而言之，这些实验将提供重要的小说 对狼疮肾损害进展的潜在疾病机制的见解，并提供潜在的 狼疮性肾炎的新治疗方法。