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 输尿管梗阻是引起急慢性肾脏疾病的常见原因，可由多种原因引起。 泌尿系统的内在和外在的病理过程。先天性颅底梗阻性畸形 尿路是慢性肾脏病(CKD)和终末期肾病(ESRD)的最常见原因 在孩子们身上。在成人中，梗阻性尿路病占急性肾功能衰竭的10%，占急性肾功能衰竭的4%。 终末期肾病5例。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长足的进步， 尤其是关于炎症、成纤维细胞激活、肾小管和微血管损伤是如何导致 纤维化，在过去的十年里已经完成了。然而，治疗纤维化疾病一直是 具有挑战性，因为这种疾病的发病机制复杂。主信号的识别或 将最初的刺激转化为纤维化发展所必需的核心途径，及其靶向 可能需要用来限制疾病的进展。我们公布的数据表明，新的范式 环氧二十碳三烯酸(EETs)刺激可完全预防梗阻性肝纤维化和炎症 肾病模型。该项目的总体目标是阐明EETs预防肾脏的机制。 并确定EET激活或增强其信号通路的翻译潜力。 根据初步数据，我们的中心假设是EETs在UUO后的肾脏和UUO后的 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 PARP1介导的TLR4、NF-κB、α、IL-1、IL-2、IL-6、IL-12的激活与白细胞黏附 分子。此外，我们的数据表明，EETS区域异构体下调P53的表达。我们的新奇数据 表明抑制P53促进脂肪酸氧化(FAO)，防止细胞内脂质积聚 预防UUO后纤维化。在UUO和其他组织中观察到FAO的缺陷和细胞内脂质堆积 CKD模型，在氧化应激、炎症、细胞死亡、表型等方面发挥重要作用 肝纤维化与慢性肾脏病。应该强调的是，P53在粮农组织或脂质堆积中的作用尚未 在任何组织或疾病状态下都有报道，并且正在CKD研究中进行范式转换。我们将确定 P53在输尿管梗阻模型中调节脂肪酸氧化的机制。我们的研究是 创新作为EETs信号转导机制的作用在肾纤维化发生中的作用 据报道。了解纤维化形成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依据，预防纤维化疾病不仅发生在肾脏 也存在于包括肝脏和心脏在内的其他器官中。