The Role of renal macrophages in recovery from renal injury

肾巨噬细胞在肾损伤恢复中的作用

• 批准号: 10194467
• 负责人: RAYMOND C. HARRIS
• 金额: $ 59.04万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-05 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194467
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Aerobic; Apoptosis; Apoptotic; Arginine; Cells; Chronic; Chronic Kidney Insufficiency; Citric Acid Cycle; Creatinine; Defect; Dendritic Cells; Development; Epithelial Cells; Etiology; Exhibits; Fc Receptor; Fibrosis; Glucose; Glutamine; Glycolysis; Growth; Inflammation; Inflammatory; Injury; Injury to Kidney; Intensive Care Units; Ischemia; Isocitrates; Kidney; Kidney Failure; Lead; Mediating; Mediation; Metabolic; Metabolism; Nature; Necrosis; Nephrons; PTGS2 gene; Patients; Phagocytes; Phagocytosis; Phase; Phenotype; Play; Population; Process; Production; Recovery; Recovery of Function; Reperfusion Therapy; Resolution; Risk; Role; Rupture; Secondary to; Serum; Stimulus; Succinates; Tissues; Toll-like receptors; Transforming Growth Factor beta Receptors; cell regeneration; chemokine; cyclooxygenase 2; cytokine; ischemic injury; kidney cell; macrophage; monocyte; neutrophil; renal epithelium; repaired; response; septic

Acute kidney injury (AKI) varies from 5% in all hospitalized patients to 30–50% in intensive care units. The proximate cause of the injury appears to be multifactorial, whether the etiology of AKI is ischemic, septic, toxic or some combination of the three. However, there is increasing evidence for an important role in AKI for both resident and infiltrating macrophages to initiate and exacerbate renal injury by polarization to a pro- inflammatory or “classically activated” (“M1”) phenotype. An unanswered question is: What are the triggers to activate quiescent resident macrophages and monocytes to an M1 phenotype following an episode of AKI? Studies by us and others have also recently demonstrated important roles for tissue reparative or “alternatively activated” (“M2”) macrophages in the recovery from AKI. M2 macrophages are phagocytes and play an important role in the phagocytosis of apoptotic epithelial cells as well as apoptotic neutrophils (“efferocytosis”). There is evidence that when apoptotic cells are not phagocytized, they may eventually rupture and release their cellular contents, a process known as “secondary necrosis”, and these cellular contents may activate viable epithelial cells and infiltrating cells through Fc receptors and toll like receptors (TLRs) and induce inflammatory cytokines. We propose that the failure of renal macrophages to effectively perform these functions is an important factor mediating development of continued inflammation and ineffective repair, which can lead to development of chronic renal insufficiency and we will address: How do M2 macrophages/dendritic cells promote renal epithelial cell repair following AKI? Alterations in metabolism play an important role in polarization of macrophages. M1 macrophages utilize predominantly glucose and glutamine as metabolic substrates, have increased aerobic (“Warburg”) glycolysis and exhibit defects in the Krebs cycle such that there is increased isocitrate, succinate and arginine production. Still unexplored is: What is the role of alterations in immunometabolism in acute kidney injury? There is also increasing evidence that apparent functional recovery from episodes of AKI can be incomplete, even if BUN and serum creatinine levels return toward normal, and the post-AKI kidney is at increased risk both for further injury and for the development of CKD. We will determine if activated, profibrotic renal M2 macrophages play a key role in development of fibrosis in the later stages of recovery from AKI? To answer these questions, we propose three specific aims: Aim 1 Determine the Mechanisms Underlying Development and Action of Proinflammatory Macrophages in Acute Kidney Injury Aim 2 Determine the Role of Immunometabolism in Acute Kidney Injury Aim 3 Determine Mechanisms Mediating Macrophage Promotion of Post-AKI Tubulointerstitial Fibrosis !

急性肾脏损伤（AKI）从所有住院患者的5％到重症监护病房的30-50％不等。 损伤的直接原因似乎是多因素的，AKI的病因是否是缺血性，化粪池， 有毒或三个组合。但是，有越来越多的证据表明在AKI中发挥重要作用 居民和渗透巨噬细胞都通过极化到促进 炎症或“经典激活”（“ M1”）表型。一个未解决的问题是：什么是触发器 在AKI发作之后，将静态居民巨噬细胞和单核细胞激活为M1表型？ 我们和其他人的研究最近还证明了组织修复或“替代地”的重要作用 激活的”（“ M2”）巨噬细胞从AKI恢复中。M2巨噬细胞是吞噬细胞，并且玩耍 在凋亡上皮细胞以及凋亡中性粒细胞的吞噬作用中的重要作用 （“肾脏细胞增多症”）。有证据表明，当凋亡细胞未被吞噬时，它们最终可能 破裂并释放其细胞含量，一种称为“继发坏死”的过程，这些细胞 内容物可能会通过FC受体激活可行的上皮细胞和浸润细胞，并像 接收器（TLR）并诱导炎症细胞因子。我们建议肾脏失败 有效执行这些功能的巨噬细胞是介导的重要因素 持续的炎症和无效修复，这可能导致慢性肾脏的发展 不足，我们将解决：M2巨噬细胞/树突细胞如何促进肾上皮 AKI后的细胞修复？代谢的改变在巨噬细胞的极化中起着重要作用。 M1巨噬细胞主要利用葡萄糖和谷氨酰胺作为代谢底物，有氧虫增加 （“ Warburg”）糖酵解并在克雷布斯周期中存在缺陷，使等酸增加，琥珀酸盐 和精氨酸产生。仍然出乎意料的是：急性中免疫代谢中改变的作用是什么 肾脏受伤？也有越来越多的证据表明，从AKI发作中明显的功能恢复可以 即使面包和血清肌酐水平恢复正常，也不完整 进一步受伤和CKD发展的风险增加。我们将确定是否激活，纤维化 肾脏M2巨噬细胞在AKI恢复的后期纤维化发展中起关键作用？到 回答这些问题，我们提出了三个具体目标： AIM 1确定促炎巨噬细胞发展和作用的机制 急性肾脏受伤 AIM 2确定免疫代谢在急性肾脏损伤中的作用 AIM 3确定介导巨噬细胞促进巨噬细胞的机制 呢