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

基本信息

批准号：
10395615
负责人：
BABU Joseph PADANILAM
金额：
$ 43.06万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-12 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395615
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 innovation interstitial kidney fibrosis male mitochondrial dysfunction novel novel therapeutic intervention prevent protective effect translational potential urinary tract obstruction

项目摘要

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，可能由多种原因引起泌尿系统先天性阻塞性异常的病理过程。泌尿道是慢性肾病（CKD）和终末期肾病（ESRD）的最常见原因在儿童中，梗阻性尿病占急性肾衰竭原因的 10%，占急性肾衰竭原因的 4%。终末期肾病病例中，肾小管间质纤维化是导致疾病的最终常见途径。我们对肾小管间质纤维化的理解取得了巨大进步，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然而，纤维化疾病的治疗已在过去十年中取得了进展。由于该疾病的主要信号或疾病的复杂发病机制的识别具有挑战性。将初始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限制疾病进展。环氧二十碳三烯酸（EET）刺激可以完全预防阻塞性纤维化和炎症肾病模型的总体目标是阐明 EET 预防肾病的机制。纤维发生并确定 EET 激活或增强其信号通路的转化潜力。根据初步数据，我们的中心假设是 UUO 后和 UUO 后肾脏中产生 EET 临床相关的慢性阻塞性肾病和释放模型可预防聚（ADP-核糖）聚合酶 1 (PARP1) 介导的 TLR4、NF-κB、TNF-α、白细胞介素 (IL) 1、2、6 和 12 的激活以及白细胞粘附此外，我们的数据表明 EET 区域异构体下调 p53 表达。表明 p53 抑制促进脂肪酸氧化 (FAO) 并防止细胞内脂质积累在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、观察到的表型中发挥重要作用纤维发生和 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下都有报道，并且是 CKD 研究的范式转变，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。 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得到证实报道称，了解纤维形成的分子机制将产生广泛的影响。为设计新的治疗策略提供基础，不仅预防肾脏纤维化疾病而且还存在于其他器官，包括肝脏和心脏。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epoxyeicosatrienoic acid administration or soluble epoxide hydrolase inhibition attenuates renal fibrogenesis in obstructive nephropathy.

给予环氧二十碳三烯酸或抑制可溶性环氧化物水解酶可减轻阻塞性肾病的肾纤维化。

DOI：
发表时间：
2023-02-01
期刊：
影响因子：
0
作者：
Noh, Mi Ra;Jang, Hee;Salem, Fadi E;Ferrer, Fernando A;Kim, Jinu;Padanilam, Babu J
通讯作者：
Padanilam, Babu J

Epoxyeicosatrienoic acid activation moderates endothelial mesenchymal transition to reduce obstructive nephropathy.

环氧二十碳三烯酸活化可调节内皮间质转化，从而减少梗阻性肾病。

DOI：
发表时间：
2017-12
期刊：
影响因子：
0
作者：
Padanilam; Babu J
通讯作者：
Babu J

Defective Mitochondrial Fatty Acid Oxidation and Lipotoxicity in Kidney Diseases.

肾脏疾病中线粒体脂肪酸氧化缺陷和脂毒性。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Jang, Hee;Noh, Mi Ra;Kim, Jinu;Padanilam, Babu J
通讯作者：
Padanilam, Babu J

Renal Sympathetic Nerve-Derived Signaling in Acute and Chronic kidney Diseases.

急性和慢性肾脏疾病中的肾交感神经衍生信号。

DOI：
发表时间：
2020-02-28
期刊：
影响因子：
5.6
作者：
Noh, Mi Ra;Jang, Hee;Kim, Jinu;Padanilam, Babu J
通讯作者：
Padanilam, Babu J

Role of α- and β-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease.

α-和β-肾上腺素能信号在表型靶向中的作用：在良性和恶性泌尿系统疾病中的意义。

DOI：
发表时间：
2021-07-20
期刊：
影响因子：
0
作者：
Archer, M;Dogra, N;Dovey, Z;Ganta, T;Jang, H;Khusid, J A;Lantz, A;Mihalopoulos, M;Stockert, J A;Zahalka, A;Björnebo, L;Gaglani, S;Noh, M R;Kaplan, S A;Mehrazin, R;Badani, K K;Wiklund, P;Tsao, K;Lundon, D J;Mohamed, N;Lucien, F;Padan
通讯作者：
Padan