Acute Renal Failure: Mechanisms and Adaptive Responses

急性肾衰竭：机制和适应性反应

• 批准号: 8218964
• 负责人: Richard A. Zager
• 金额: $ 38.28万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8218964
• 关键词: Abate; Acetylation; Acetyltransferase; Actins; Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Address; Animals; Area; Attention; Binding; Blood; Brain; CCL2 gene; Calcium; Cause of Death; Cell Death; Cells; Data; Employee Strikes; Endotoxins; Event; Exons; Gene Expression; Gene Targeting; Genes; Genomics; Glean; Globin; Hand; Heart; Histones; Human; Hydrolysis; Hydroxymethylglutaryl-CoA reductase; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Investigation; Ischemia; Kidney; Kidney Diseases; Knowledge; Laboratories; Ligands; Lipopolysaccharides; Liver; Lung; Lysine; Maintenance; Memory; Messenger RNA; Methyltransferase; Modeling; Modification; NF-kappa B; Nephrotoxic; Organ; Organ failure; Oxidative Stress; Pathway interactions; Patients; Pattern; Phase; Phospholipase; Phospholipids; Polymerase; Positioning Attribute; Production; Promoter Regions; RNA Polymerase II; Reaction; Recovery; Renal Tissue; Resistance; Resolution; Rest; Role; Sepsis; Small Interfering RNA; Staging; Stimulus; System; TNF gene; Testing; Tissues; Toll-like receptors; Transcription Factor AP-1; Tubular formation; Variant; Venous; cell injury; chemokine; chromatin remodeling; clinically relevant; cytokine; heme oxygenase-1; histone modification; in vivo; injured; insight; interest; oncology; oxidant stress; programs; promoter; prototype; renal ischemia; research study; response; slow potential; tool; transcription factor

DESCRIPTION (provided by applicant): A seeming paradox exists during the maintenance phase of acute renal failure (ARF). On the one hand, diverse forms of acute tubular injury evoke adaptive responses that protect the kidney from further damage (so called "acquired cytoresistance"). Presumably, this protection confers a survival advantage, both at the whole organ, and whole animal, level. On the other hand, a potentially countervailing consequence of ARF is that the kidney hyper-responds to diverse Toll like receptor (TLR) ligands, most notably lipopolysaccharide (LPS). This causes exaggerated LPS- driven cytokine and chemokine (e.g., TNF-a / MCP- 1) production. As a result, profound increases in intra-renal levels of these pro-inflammatory mediators develop, potentially slowing ARF recovery. Furthermore, with cytokine efflux into renal venous blood, striking increases in circulating cytokine / chemokine levels develop. This can contribute to extra-renal tissue damage (e.g., in lung, liver, heart, and brain; i.e., "organ cross-talk"), and thus, predispose to multi-organ failure (MOF). The clinical relevance of these events is underscored by the fact that Gram negative sepsis and MOF are leading causes of death in patients with ARF. This application hypothesizes that these two ARF maintenance phase phenomena (cytoresistance; TLR hyper-responsiveness) are examples of "biologic memory": i.e., whereby one episode of renal injury 're-programs' the kidney to 'remember' the initial insult, and thus, produce altered tissue responses upon re-challenge. Over the past 3 years, the PI has tested the hypothesis that this "biologic memory" is expressed at the genomic level, and that these genomic changes help determine how the ARF kidney responds to subsequent insults. To support this concept, we have identified "activating" histone changes at specific genes that participate in both acquired cytoresistance (heme oxygenase 1, HMG CoA reductase), and the hyper-inflammatory state (TNF-a; MCP-1). During the resolution phase of ARF, the histone changes at these pro-inflammatory genes and their cognate mRNAs progressively increase. Conversely, cytoresistant gene expression progressively abates. These reciprocal shifting patterns, i.e., increasing inflammatory gene expression / decreasing cytoresistance gene expression, can delay ARF recovery. Hence, the overall aims of the proposed investigation are as follows: 1. Delineate which specific cell injury pathways (e.g., ATP depletion, oxidant stress, phospholipid hydrolysis) are the initial stimuli that trigger downstream histone alterations; 2. Determine whether histone changes occur at test gene promoter regions, and whether hyper-recruitment of relevant transcription factors and of RNA polymerase II (Pol II) to them result; 3. Ascertain the histone-modifying machineries that induce these histone alterations; and 4. Using the information gleaned from the above, test the mechanistic relevance of these pathways to the cytoresistance and the hyper-inflammatory states. By so doing, new insights into ischemia- induced tissue modifications, with implications for subsequent tissue injury, will result. PUBLIC HEALTH RELEVANCE: This application addresses how pre-existent acute kidney injury alters how the kidney responds to further injury events. One the one hand, pre-existent injury ushers in protective mechanisms that mitigate further lethal damage; on the other hand, the injured kidney hyper-responds to inflammatory molecules, and this has implications for both the kidney and the rest of the body. This application addresses the mechanisms by which these changes occur, and how they can be altered to enhance kidney recovery.

描述（由申请人提供）：在急性肾衰竭（ARF）的维护阶段存在一个看似悖论。一方面，各种形式的急性管状损伤引起了保护肾脏免受进一步损害的适应性反应（所谓的“获得的细胞耐药”）。据推测，这种保护在整个器官和整个动物水平上都具有生存优势。另一方面，ARF的潜在反击后果是肾脏超反应对多种受体（TLR）配体，最著名的是脂多糖（LPS）。这会导致夸张的LPS驱动的细胞因子和趋化因子（例如TNF-A / MCP-1）生产。结果，这些促炎性介体的肾脏内水平的深刻增加可能会减慢ARF恢复。此外，随着细胞因子外排成肾静脉血，循环细胞因子 /趋化因子水平的醒目增加。这可以导致肾外组织损伤（例如，在肺，肝脏，心脏和大脑中；即“器官交叉对话”），因此倾向于多器官衰竭（MOF）。这些事件的临床相关性突显了革兰氏阴性败血症和MOF是ARF患者的死亡原因。该应用假设这两种ARF维护相现象（细胞震动； TLR高反应性）是“生物记忆”的示例：即，肾脏损伤的一集重新编程“记住”肾脏“记住”最初的侮辱，从而产生对重新核能的组织反应改变的组织反应。在过去的三年中，PI检验了以下假设：这种“生物记忆”在基因组水平上表达，并且这些基因组变化有助于确定ARF肾脏对随后的损伤的反应。为了支持这一概念，我们已经确定了参与获得的细胞耐药性（血红素加氧酶1，HMG COA还原酶）和高炎症态（TNF-A; MCP-1）的特定基因的“激活”组蛋白变化。在ARF的分辨率阶段，组蛋白在这些促炎基因及其同源mRNA逐渐增加。相反，细胞抗性基因表达逐渐减轻。这些相互转移的模式，即增加炎症基因表达 /降低细胞扰动基因表达，可能会延迟ARF恢复。因此，拟议研究的总体目的如下：1。描述哪种特定的细胞损伤途径（例如ATP耗竭，氧化剂应激，磷脂水解）是触发下游组蛋白改变的初始刺激； 2。确定在测试基因启动子区域发生的组蛋白是否发生，以及相关转录因子和RNA聚合酶II（POL II）的超摄氏度是否结果； 3。确定诱导这些组蛋白改变的组蛋白修饰机器；和4。使用从上述收集的信息，测试这些途径与细胞耐药性和过度炎症状态的机械相关性。通过这样做，将会导致对缺血诱导的组织修饰的新见解，对随后的组织损伤产生影响。 公共卫生相关性：该申请解决了先前急性肾脏损伤如何改变肾脏对进一步伤害事件的反应。一方面，先前存在的伤害引起了保护性机制，从而减轻了致命的损害；另一方面，受伤的肾脏超声反应对炎症分子，这对肾脏和身体的其余部分都有影响。该应用程序解决了发生这些变化的机制，以及如何改变它们以增强肾脏的恢复。