Reno-protective mechanisms of EETs in acute and chronic obstructive nephropathy

EETs对急慢性梗阻性肾病的肾脏保护机制

• 批准号: 10309331
• 负责人: BABU Joseph PADANILAM
• 金额: $ 43.17万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-12 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10309331
• 关键词: Acids; Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Anti-Inflammatory Agents; Apoptotic; Arachidonic Acids; Attenuated; Automobile Driving; Binding; Biological; Cell Death; Cell Nucleus; Child; Chronic; Chronic Kidney Failure; Complex; Consequentialism; Data; Defect; Deposition; Development; Disease; Disease Progression; Disease model; Down-Regulation; End stage renal failure; Epoxide hydrolase; Female; Fibroblasts; Fibrosis; Genes; Genetic; Genetic Transcription; Goals; Heart; Hydrolysis; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Intracellular Accumulation of Lipids; Kidney; Kidney Diseases; Knockout Mice; Lead; Leukocyte Adhesion Molecules; Lipids; Liver; Lung; Mediating; Mitochondria; Mitochondrial Matrix; Modeling; Molecular; Mus; Nuclear; Organ; Oxidative Stress; PPAR alpha; PPAR gamma; Pathogenesis; Pathologic Processes; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Poly(ADP-ribose) Polymerases; Process; Production; Proteins; Publishing; Reactive Oxygen Species; Reporting; Research; Role; Scheme; Seminal; Signal Pathway; Signal Transduction; Stimulus; TLR4 gene; TNF gene; TP53 gene; Testing; Tissues; Tubular formation; Ureteral obstruction; Urinary system; Urinary tract; Vasodilation; Virulence Factors; base; clinically relevant; cyclophilin D; design; fatty acid oxidation; fibrogenesis; inhibitor/antagonist; innovation; interstitial; kidney fibrosis; male; mitochondrial dysfunction; novel; novel therapeutic intervention; prevent; protective effect; urinary tract obstruction

Abstract/Project Summary Ureteral obstruction is a common cause of acute and chronic kidney disease and may result from a wide variety of pathologic processes, intrinsic and extrinsic to the urinary system. Congenital obstructive anomalies of the urinary tract are the most common cause of chronic kidney disease (CKD) and end stage renal disease (ESRD) in children. In adults, obstructive uropathy accounts for 10% of the causes of acute renal failure and 4% of the cases of end stage renal disease. Tubulointerstitial fibrosis is the final common pathway that leads to disease progression and end-stage renal disease. Great strides in our understanding of renal tubulointerstitial fibrosis, particularly as to how inflammation, fibroblast activation, tubular and microvascular injury contribute to fibrogenesis, have been accomplished in the past decade. However, treating fibrotic diseases has been challenging because of the complex pathogenesis of the disease. Identification of the primary signals or the core pathway that is essential to convert an initial stimulus to the development of fibrosis, and their targeting may be required to limit disease progression. Our published data indicate the novel paradigm that epoxyeicosatrienoic acids (EETs) stimulation can completely prevent fibrosis and inflammation in obstructive nephropathy models. The overall project goal is to elucidate the mechanisms by which EETs prevent renal fibrogenesis and determine the translational potential of EET activation or augmenting its signaling pathways. Based on preliminary data, our central hypothesis is that EETs produced in the kidney after UUO and in the clinically relevant chronic obstructive nephropathy and release models prevent poly (ADP-ribose) polymerase 1 (PARP1)-mediated activation of TLR4, NF-κB, TNF-α, interleukin (IL) 1, 2, 6 and 12 and leukocyte adhesion molecules. Further, our data indicate that EETs regioisomers down-regulate p53 expression. Our novel data indicate that p53 inhibition promotes fatty acid oxidation (FAO) and prevents intracellular lipid accumulation to prevent fibrosis after UUO. Defects in FAO and intracellular lipid accumulation are observed in UUO and other CKD models and has an important role in oxidative stress, inflammation, cell death, phenotypes observed in fibrogenesis and CKD. It should be emphasized that a role for p53 in FAO or lipid accumulation has not been reported in any tissue or disease state and is paradigm shifting in CKD research. We will determine the mechanism by which p53 regulates fatty acid oxidation in ureteral obstruction models. Our studies are innovative as a role for EETs signaling as a primary mechanism instigating renal fibrogenesis has not been reported. Understanding the molecular mechanisms of fibrogenesis will have wide implications as they may provide the basis for designing novel therapeutic strategies, to prevent fibrotic diseases not only in the kidney but also in other organs including the liver and heart.

摘要/项目摘要 输尿管阻塞是急性和慢性肾脏疾病的常见原因，可能是由于种类繁多的 病理过程，尿液系统内在和外在的。先天性阻塞性异常 尿路是慢性肾脏疾病（CKD）和终阶段肾脏疾病（ESRD）的最常见原因 在儿童中。在成年人中，阻塞性泌尿病占急性肾衰竭原因的10％和4％ 末期肾脏疾病的病例。微管间质纤维化是导致疾病的最终常见途径 进展和终末期肾脏疾病。在我们对肾小管纤维化纤维化的理解方面的大步迈进 特别是关于感染，成纤维细胞激活，管状和微血管损伤如何有助于 纤维发生，在过去十年中已经完成。但是，治疗纤维化疾病已经 由于疾病的发病机理而具有挑战性。识别主要信号或 将初始刺激转换为纤维化的发展至关重要的核心途径及其靶向 可能需要限制疾病进展。我们发布的数据表明了新颖的范式 环氧酸性酸（EET）刺激可以完全预防阻塞性纤维化和炎症 肾病模型。总体项目目标是阐明Eets防止肾脏的机制 纤维发生并确定EET激活或增强其信号通路的翻译潜力。 基于初步数据，我们的中心假设是在UUO之后和在肾脏中产生的Eets和 临床相关的慢性阻塞性肾病和释放模型预防聚（ADP-核糖）聚合酶1 （PARP1）介导的TLR4，NF-κB，TNF-α，白介素（IL）1、2、6和12的激活以及白细胞粘附 分子。此外，我们的数据表明eets rycioisomaters下调p53表达。我们的新数据 表明p53抑制作用促进脂肪酸氧化（FAO），并防止细胞内脂质积累到 在UUO之后预防纤维化。在UUO和其他方面观察到粮农组织和细胞内脂质积累的缺陷 CKD模型，在氧化应激，感染，细胞死亡，表型中具有重要作用 纤维发生和CKD。应该强调的是，p53在粮农组织或脂质积累中的作用尚未 在任何组织或疾病状态下报道，是CKD研究中的范式转移。我们将确定 p53在输尿管反对模型中调节脂肪酸氧化的机制。我们的研究是 创新作为Eets信号作为作为启发肾纤维发生的主要机制的作用 报告。了解纤维化的分子机制将具有广泛的影响 提供设计新型热策略的基础，以防止纤维化疾病不仅在肾脏中 而且还包括肝脏和心脏在内的其他器官。