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: 9765295
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765295
• 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; Natural regeneration; 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; chemokine; cyclooxygenase 2; cytokine; kidney cell; macrophage; monocyte; neutrophil; 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 !

急性肾损伤(AKI)在所有住院患者中占5%，在重症监护病房中占30%至50%。 损伤的直接原因似乎是多因素的，无论AKI的病因是缺血，败血症， 有毒的或三者的某种组合。然而，越来越多的证据表明，在AKI中， 驻留巨噬细胞和浸润性巨噬细胞通过极化至亲肾细胞而启动和加重肾损伤。 炎症性或“典型激活”(“M1”)表型。一个悬而未决的问题是：触发因素是什么 AKI发作后，激活静止的驻留巨噬细胞和单核细胞至M1表型？ 我们和其他人的研究最近也证明了组织修复或 活化的“M2”巨噬细胞在AKI复苏过程中的作用。M2巨噬细胞是吞噬细胞，扮演着 在吞噬凋亡的上皮细胞和凋亡的中性粒细胞中的重要作用 (“胞泡增多症”)。有证据表明，当凋亡细胞没有被吞噬时，它们最终可能 破裂并释放其细胞内容物，这一过程被称为“继发性坏死”，而这些细胞 内容物可能通过Fc受体和Toll样蛋白激活活的上皮细胞和浸润性细胞 受体(TLR)和诱导炎性细胞因子。我们认为肾功能衰竭 巨噬细胞有效地执行这些功能是介导糖尿病发生的重要因素。 持续的炎症和无效的修复，可导致慢性肾脏的发展 不足，我们将解决：M2巨噬细胞/树突状细胞如何促进肾上皮细胞 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，增加了有氧 (“Warburg”)糖酵解，在Krebs循环中表现出缺陷，导致异柠檬酸、琥珀酸增加 和精氨酸生产。目前尚不清楚的是：急性胰腺炎患者免疫代谢改变的作用是什么？ 肾损伤？越来越多的证据表明，急性心肌梗死发作后明显的功能恢复可以 是不完整的，即使BUN和血肌酐水平恢复正常，AKI后肾脏处于 增加进一步受伤和发展为慢性肾脏病的风险。我们将确定激活的、促纤维化的 肾M_2巨噬细胞在急性肾损伤后期纤维化的发生发展中起关键作用。至 为了回答这些问题，我们提出了三个具体目标： 目的1确定促炎性巨噬细胞的发育和作用机制。 急性肾损伤 目的2确定免疫代谢在急性肾损伤中的作用 目的3确定巨噬细胞促进急性肾损伤后肾小管间质纤维化的机制。 好了！