Targeting oxidative stress modifiers in acute kidney injury

针对急性肾损伤的氧化应激调节剂

基本信息

批准号：
8074925
负责人：
HAMID RABB
金额：
$ 38.26万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8074925
关键词：
Acute Renal Failure with Renal Papillary Necrosis Antioxidants Biology Bone Marrow Bone Marrow Cells Cell Culture Techniques Cell Nucleus Cell physiology Chimera organism Cisplatin Clinical Clinical Trials Collaborations Complex Crossbreeding Cytoplasm Data Development Disease Enzymes Epithelial Epithelial Cells Epithelium Experimental Models Foundations Functional disorder Future Gene Expression Gene Targeting Genes Genetic Histology Hypoxia Immune response In Vitro Incidence Inflammation Inflammatory Response Injury Institution Ischemia Joint Ventures Kidney Kidney Transplantation Laboratories Lead Leukocytes Mediating Mediator of activation protein Modeling Molecular Morbidity - disease rate Muramidase Mus Myelogenous Nephrotoxic Nitrogen Nuclear Translocation Outcome Oxidants Oxidative Stress Oxygen Pathogenesis Pathway interactions Patients Physicians Positioning Attribute Predisposition Preventive Process RNA Interference Reactive Oxygen Species Reagent Regulation Renal function Reperfusion Therapy Research Response Elements Role Scientist Signal Transduction Stimulus Supplementation Testing Therapeutic Therapeutic Agents Tissues Transgenic Mice Translations Tubular formation Vascular Permeabilities Work base cell injury cost defined contribution health care service utilization improved in vivo inhibitor/antagonist injury and repair innovation insight kidney cell mortality mouse model multidisciplinary mutant novel novel therapeutic intervention novel therapeutics nucleocytoplasmic transport promoter public health relevance response response to injury small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) caused either by ischemia reperfusion (IR) or by a nephrotoxin is common in hospitalized patients and is associated with an overall mortality rate of up to 50% in the ICU, Despite the high incidence and high mortality rate, there is no specific treatment and the pathophysiology is incompletely understood. Emerging evidence suggests that an antioxidant and oxidant imbalance (or oxidative stress) leading to cell injury, inflammatory, and immune responses participates in the pathogenesis of AKI. Thus, identifying and understanding the functions and regulation of molecular effectors that regulate oxidative stress in response to ischemic and nephrotoxic insults could lead to novel therapeutic opportunities in AKI. In preliminary studies, we found that mice with genetic disruption of Nrf2 (a b-ZIP transcription factor critical for the induction of several antioxidant and cytoprotective gene expression) are more susceptible to IRI-induced vascular permeability and inflammatory responses, as compared with wild type (Nrf2+/+) mice. Nrf2-deficient (Nrf2-/-) mice were also more susceptible to cisplatin-induced nephrotoxic AKI as compared to wild type controls. Antioxidant supplementation significantly improved renal function and histology in Nrf2-/- mice. Based on these preliminary data, we hypothesize that endogenous Nrf2 confers protection in AKI and augmentation of Nrf2 activity is a potential protective strategy for both ischemic and nephrotoxic AKI. As the translocation of Nrf2 from the cytoplasm to the nucleus is critical for ARE- mediated transcriptional response following stressful stimuli, we propose that perturbation in either specific signaling or factors controlling the Nrf2 expression and activation can result in lower levels of antioxidant enzyme expression, thereby contributing to and/or enhancing suscepitibility to the development of AKI. To test these hypotheses, we propose the following three specific aims: 1) Elucidate molecular mechanisms (upstream signals) that control the activation of Nrf2 in response to ischemia reperfusion, 2) Define the contribution of oxidative stress elicited by infiltrating leukocytes compared to resident kidney cells in the development and/or perpetuation of AKI using gene targeted Nrf2 mice, and 3) Determine whether boosting Nrf2 activation using a pharmacologic and a genetic approach confers protection against AKI. Our overall findings obtained from genetically manipulated mouse models and cell culture studies should yield extremely important insights underlying AKI and could have important implications to identify the effector mechanisms causing susceptibility to AKI. The application is developed in a multidisciplinary team approach combining strengths in transcriptional biology, in vitro and in vivo AKI models, and inflammation. PUBLIC HEALTH RELEVANCE: Acute kidney injury is a major cause of mortality, morbidity, and health care utilization cost. The current proposal utilizes both cell culture and genetically manipulated mouse models, and novel reagents to elucidate the mechanisms and therapeutic potential of the Nrf2-Keap-ARE pathway that regulate antioxidant and oxidant imbalance (oxidative stress) during AKI in mice. The proposed studies will provide strong foundation to enable us to target the Nrf2-Keap1-ARE pathway for future clinical trials in acute kidney injury.

描述（由申请人提供）：由缺血再灌注（IR）或肾毒素引起的急性肾脏损伤（AKI）在住院的患者中很常见，尽管ICU的总死亡率高达50％，但仍与高达50％发病率和高死亡率，没有特定的治疗方法，并且病理生理学尚未完全理解。新兴证据表明，导致细胞损伤，炎症和免疫反应的抗氧化剂和氧化剂失衡（或氧化应激）参与AKI的发病机理。因此，识别和理解分子效应子的功能和调节，这些功能和调节因缺血性和肾毒性损伤而调节氧化应激可能会导致AKI的新治疗机会。在初步研究中，我们发现具有NRF2遗传破坏的小鼠（B-ZIP转录因子对于诱导几种抗氧化剂和细胞保护基因表达至关重要）更容易受到iri诱导的血管通透性和炎症反应的影响，与野生型相比（NRF2+/+）小鼠。与野生型对照相比，NRF2缺陷型（NRF2 - / - ）小鼠也更容易受到顺铂诱导的肾毒性AKI的影响。 NRF2 - / - 小鼠中的抗氧化剂补充剂可显着改善肾功能和组织学。基于这些初步数据，我们假设内源性NRF2在AKI中赋予保护，而NRF2活性的增强是缺血性和肾毒性AKI的潜在保护策略。由于NRF2从细胞质到核的易位对于压力刺激后的介导的转录反应至关重要，因此我们提出，在特定信号传导或控制NRF2表达和激活的因素中扰动会导致抗氧化剂酶表达的水平较低，从而导致其水平为AKI的发展做出贡献和/或增强可疑性。为了检验这些假设，我们提出以下三个特定目的：1）阐明分子机制（上游信号）控制NRF2对缺血再灌注的激活，2）定义与浸入的白细胞相比引起的氧化应激的贡献使用具有基因的NRF2小鼠的AKI发育和/或永续存在的细胞，以及3）确定使用药理学和遗传方法促进NRF2激活是否赋予对AKI的保护。我们从遗传操纵的小鼠模型和细胞培养研究中获得的总体发现应产生AKI的极为重要的见解，并可能具有重要的含义，以识别导致对AKI敏感的效应机制。该应用是在多学科团队方法中开发的，该方法结合了转录生物学，体外和体内AKI模型以及炎症的优势。公共卫生相关性：急性肾脏损伤是导致死亡率，发病率和医疗保健利用成本的主要原因。当前的建议同时利用细胞培养和遗传操纵的小鼠模型，以及新的试剂来阐明NRF2-KEAP-ARE途径的机制和治疗潜力，从而调节小鼠中AKI期间AKI期间调节抗氧化剂和氧化应激（氧化应激）。拟议的研究将为我们提供良好的基础，使我们能够针对NRF2-KEAP1-ARE途径，以实现急性肾脏损伤的未来临床试验。