Mechanisms of iron-mediated renal injury in lupus nephritis

项目概要/摘要 狼疮是一种慢性的，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（狼疮性肾炎）是狼疮的严重和常见并发症，影响约50%的 患者，并已与不良的患者预后和过早死亡的风险增加。电流 狼疮的治疗是基于抑制免疫系统和炎症。可惜这些 包括皮质类固醇在内的治疗具有严重的副作用， 保护肾脏，强调需要新的治疗方法。铁是一个重要的组成部分， 身体，但当存在过量可能会导致细胞损伤。有证据表明，铁代谢可能是 在狼疮患者的肾脏异常，越来越多的文献表明，几个铁 代谢蛋白可以作为狼疮性肾炎的尿生物标志物。我们发布的报告显示， 肾脏中的铁积累增加，降低体内铁水平有助于保护肾脏。 在狼疮性肾炎的小鼠模型中，该提案调查了 铁促进狼疮肾损伤的机制，我们的目标是特异性阻断这些机制， 破坏作用，同时维持正常的铁稳态。具体来说，我们认为在狼疮性肾炎中， 铁源（包括转铁蛋白）的增强的过滤导致肾小球和肾小管损伤，包括铁- 诱导细胞死亡（铁凋亡），促进狼疮性肾炎肾损伤的进展。铁蛋白沉着症是 一种最近描述的细胞死亡形式，从未在狼疮中进行过研究或靶向。我们的初步数据 表明铁凋亡关键介质之一，酰基辅酶A合成酶长链家族成员 4（ACSL 4），在小鼠白蛋白尿发作前后在肾小球和肾小管中显著上调 随着损伤的进展，进一步增加。我们将进行基因实验， 狼疮性肾炎的诱导小鼠模型，以测试铁和ACSL 4在促进肾小球和 狼疮性肾炎中肾小管损伤，以及是否药物靶向铁积累或铁中毒的球员， 可以阻止肾损伤的进一步发展。总之，这些实验将提供重要的新的 深入了解狼疮肾损伤进展的疾病机制，并提供潜在的 狼疮性肾炎的治疗方法

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.