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）：急性肾衰竭（ARF）维持阶段存在看似矛盾的现象。一方面，多种形式的急性肾小管损伤会引起适应性反应，保护肾脏免受进一步损伤（所谓的“获得性细胞抵抗”）。据推测，这种保护在整个器官和整个动物水平上赋予了生存优势。另一方面，ARF 的一个潜在的抵消后果是肾脏对多种 Toll 样受体 (TLR) 配体，尤其是脂多糖 (LPS) 过度反应。这会导致 LPS 驱动的细胞因子和趋化因子（例如 TNF-a/MCP-1）产生过多。结果，这些促炎介质的肾内水平显着增加，可能会减缓 ARF 的恢复。此外，随着细胞因子流入肾静脉血，循环细胞因子/趋化因子水平显着增加。这可能会导致肾外组织损伤（例如肺、肝、心脏和大脑；即“器官串扰”），从而导致多器官衰竭（MOF）。革兰氏阴性败血症和 MOF 是 ARF 患者死亡的主要原因，这一事实强调了这些事件的临床相关性。该应用假设这两种 ARF 维持阶段现象（细胞抵抗；TLR 高反应性）是“生物记忆”的例子：即肾损伤的一次发作“重新编程”肾脏以“记住”最初的损伤，并且因此，在再次挑战时会产生改变的组织反应。在过去的 3 年里，PI 测试了这样的假设：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 肾脏如何应对随后的损伤。为了支持这一概念，我们确定了参与获得性细胞抵抗（血红素加氧酶 1、HMG CoA 还原酶）和高炎症状态（TNF-a；MCP-1）的特定基因的“激活”组蛋白变化。在 ARF 的消退阶段，这些促炎基因及其同源 mRNA 的组蛋白变化逐渐增加。相反，细胞抗性基因表达逐渐减弱。这些相互转变的模式，即增加炎症基因表达/减少细胞抗性基因表达，可以延迟 ARF 恢复。因此，本研究的总体目标如下： 1. 明确哪些特定的细胞损伤途径（例如 ATP 耗竭、氧化应激、磷脂水解）是触发下游组蛋白改变的初始刺激； 2. 确定测试基因启动子区域是否发生组蛋白变化，以及是否导致相关转录因子和RNA聚合酶II（Pol II）过度招募； 3. 确定引起这些组蛋白改变的组蛋白修饰机制； 4.使用从上面收集的信息，测试这些途径与细胞抵抗和高炎症状态的机制相关性。通过这样做，将产生对缺血引起的组织改变的新见解，以及对随后的组织损伤的影响。 公众健康相关性：本申请解决了先前存在的急性肾损伤如何改变肾脏对进一步损伤事件的反应。一方面，预先存在的伤害带来了保护机制，可以减轻进一步的致命伤害；另一方面，受伤的肾脏对炎症分子反应过度，这对肾脏和身体其他部位都有影响。该申请解决了这些变化发生的机制，以及如何改变它们以增强肾脏恢复。