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 输尿管梗阻是急性和慢性肾脏疾病的常见原因， 病理过程，内在的和外在的泌尿系统。先天性阻塞性畸形 尿路是慢性肾病（CKD）和终末期肾病（ESRD）的最常见原因 小儿在成人中，梗阻性尿路病占急性肾衰竭原因的10%，占急性肾衰竭原因的4%。 例终末期肾病。肾小管间质纤维化是导致疾病的最终共同途径 进展和终末期肾病。我们对肾小管间质纤维化的理解有了很大的进步， 特别是炎症、成纤维细胞活化、肾小管和微血管损伤如何导致 纤维化，在过去的十年中已经完成。然而，治疗纤维化疾病一直是一个难题。 由于该疾病的发病机制复杂，因此具有挑战性。识别主要信号或 核心途径，其对于将初始刺激转化为纤维化发展至关重要，以及它们的靶向 可能需要限制疾病进展。我们公布的数据表明， 环氧二十碳三烯酸（ESTs）刺激可以完全防止阻塞性肺组织中的纤维化和炎症。 肾病模型。项目的总体目标是阐明依地平预防肾损害的机制。 纤维化和确定EET激活或增强其信号传导途径的翻译潜力。 根据初步数据，我们的中心假设是，Ekaline在UUO后的肾脏中产生， 临床相关的慢性阻塞性肾病和释放模型阻止聚（ADP-核糖）聚合酶1 （PARP 1）介导的TLR 4、NF-κB、TNF-α、白细胞介素（IL）1、2、6和12的活化和白细胞粘附 分子。此外，我们的数据表明，Escherichia regioisomers下调p53表达。我们的新数据 表明p53抑制促进脂肪酸氧化（FAO）并阻止细胞内脂质积累， 预防UUO后纤维化。在UUO和其他细胞中观察到FAO缺陷和细胞内脂质积累。 CKD模型，并在氧化应激、炎症、细胞死亡、 纤维化和CKD。应该强调的是，p53在FAO或脂质积累中的作用尚未被证实。 在任何组织或疾病状态中报告，并且是CKD研究的范式转变。康贝特人将以 p53调控输尿管梗阻模型中脂肪酸氧化的机制。我们的研究是 EET信号传导作为引发肾纤维化的主要机制的创新作用尚未被发现 报道了解纤维发生的分子机制将具有广泛的意义，因为它们可能 为设计新的治疗策略提供基础，不仅在肾脏中预防纤维化疾病， 也会影响其他器官包括肝脏和心脏。