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

基本信息

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
项目类别：
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

项目摘要

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) 的发生率从所有住院患者的 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、脓毒症、然而，越来越多的证据表明，AKI 中具有重要作用。常驻巨噬细胞和浸润巨噬细胞均通过极化为亲巨噬细胞来引发和加重肾损伤炎症或“经典激活”（“M1”）表型的一个尚未解答的问题是：触发因素是什么。 AKI 发作后将静止的巨噬细胞和单核细胞激活至 M1 表型？我们和其他人的研究最近也证明了组织修复或“替代疗法”的重要作用 AKI 恢复过程中“激活的”（“M2”）巨噬细胞 M2 巨噬细胞是吞噬细胞，发挥着重要作用。在凋亡上皮细胞和凋亡中性粒细胞的吞噬作用中发挥重要作用（“胞吞作用”）有证据表明，当凋亡细胞不被吞噬时，它们最终可能会被吞噬。破裂并释放其细胞内容物，这一过程称为“继发性坏死”，并且这些细胞内容物可能通过 Fc 受体和 toll 样激活活的上皮细胞和浸润细胞受体（TLR）并诱导炎症细胞因子，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育的重要因素持续的炎症和无效的修复，可能导致慢性肾病的发展不足，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发挥重要作用。 M1巨噬细胞主要利用葡萄糖和谷氨酰胺作为代谢底物，增加了有氧运动（“Warburg”）糖酵解并在克雷布斯循环中表现出缺陷，导致异柠檬酸、琥珀酸增加尚未探索的是：免疫代谢的改变在急性发作中的作用是什么。肾损伤？还有越来越多的证据表明 AKI 发作后的明显功能恢复可以即使 BUN 和血清肌酐水平恢复正常，并且 AKI 后肾脏处于进一步损伤和发展为 CKD 的风险增加。我们将确定是否激活、促纤维化。肾脏 M2 巨噬细胞在 AKI 恢复后期的纤维化发展中发挥关键作用？回答这些问题，我们提出三个具体目标：目标 1 确定促炎巨噬细胞发育和作用的潜在机制急性肾损伤目标 2 确定免疫代谢在急性肾损伤中的作用目标 3 确定介导巨噬细胞促进 AKI 后肾小管间质纤维化的机制！