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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：
8470636
负责人：
HAMID RABB
金额：
$ 37.24万
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/8470636
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.

描述（由申请人提供）：急性肾损伤（AKI）由缺血再灌注（IR）或肾毒素引起，在住院患者中很常见，在ICU中与总死亡率高达50%相关，尽管发病率和死亡率高，但没有特定的治疗方法，病理生理学尚不完全清楚。新出现的证据表明，导致细胞损伤、炎症和免疫反应的抗氧化和氧化失衡（或氧化应激）参与了AKI的发病机制。因此，识别和理解在缺血和肾毒性损伤下调节氧化应激的分子效应物的功能和调控可能会为AKI带来新的治疗机会。在初步研究中，我们发现，与野生型（Nrf2+/+）小鼠相比，Nrf2（一种对诱导几种抗氧化和细胞保护基因表达至关重要的b-ZIP转录因子）基因破坏的小鼠更容易受到iri诱导的血管通透性和炎症反应的影响。与野生型对照相比，Nrf2缺陷（Nrf2-/-）小鼠也更容易发生顺铂诱导的肾毒性AKI。补充抗氧化剂可显著改善Nrf2-/-小鼠的肾功能和组织学。基于这些初步数据，我们假设内源性Nrf2在AKI中具有保护作用，增强Nrf2活性是缺血性和肾毒性AKI的潜在保护策略。由于Nrf2从细胞质到细胞核的易位对于应激刺激后ARE介导的转录反应至关重要，我们提出，控制Nrf2表达和激活的特定信号或因素的扰动可导致抗氧化酶表达水平降低，从而促进和/或增加AKI的易感性。为了验证这些假设，我们提出以下三个具体目标：1)阐明在缺血再灌注时控制Nrf2激活的分子机制（上游信号）；2)利用基因靶向Nrf2小鼠，确定浸润白细胞引起的氧化应激在AKI的发生和/或延续中的作用，而不是由常驻肾细胞引起的氧化应激；3)确定通过药理学和遗传学方法增强Nrf2激活是否能保护AKI。我们从基因操纵小鼠模型和细胞培养研究中获得的总体发现应该对AKI的基础有极其重要的见解，并可能对确定引起AKI易感性的效应机制具有重要意义。该应用程序是在一个多学科团队的方法中开发的，结合了转录生物学，体外和体内AKI模型以及炎症的优势。