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 !

急性肾损伤（阿基）从所有住院患者的5%到重症监护病房的30-50%不等。 损伤的近因似乎是多因素的，无论阿基的病因是缺血性的、脓毒性的， 有毒或三者的混合物。然而，越来越多的证据表明， 驻留和浸润巨噬细胞通过极化为亲- 炎性或“经典活化”（“M1”）表型。一个尚未回答的问题是： 在阿基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“替代”的重要作用。 活化的”（“M2”）巨噬细胞在从阿基恢复中的作用。M2巨噬细胞是吞噬细胞， 在凋亡上皮细胞和凋亡中性粒细胞的吞噬作用中起重要作用 （“胞质发热”）。有证据表明，当凋亡细胞不被吞噬时，它们最终可能 破裂并释放其细胞内容物，这一过程称为“继发性坏死”，这些细胞 内容物可以通过Fc受体和Toll样受体激活活的上皮细胞和浸润细胞， 受体（TLR）并诱导炎性细胞因子。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发展的重要因素， 持续的炎症和无效的修复，这可能导致慢性肾脏病的发展 我们将解决：M2巨噬细胞/树突状细胞如何促进肾上皮细胞 阿基后的细胞修复代谢的改变在巨噬细胞的极化中起重要作用。 M1巨噬细胞主要利用葡萄糖和谷氨酰胺作为代谢底物， （“瓦尔堡”）糖酵解并在克雷布斯循环中表现出缺陷，使得异柠檬酸、琥珀酸 和精氨酸生产。尚未探索的是：急性胰腺炎中免疫代谢改变的作用是什么 肾损伤？也有越来越多的证据表明，从阿基发作中明显的功能恢复可以 即使尿素氮和血清肌酸酐水平恢复正常，并且AKI后肾脏处于 进一步损伤和CKD发展的风险增加。我们将确定是否激活，促纤维化 肾M2巨噬细胞在阿基恢复后期的纤维化发展中起关键作用？到 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生成和作用的机制 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确定介导巨噬细胞促进AKI后肾小管间质纤维化的机制 !