Targeting oxidative stress modifiers in acute kidney injury

针对急性肾损伤的氧化应激调节剂

• 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
• 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

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(申请人提供)：急性肾损伤(AKI)，无论是由缺血再灌注(IR)或由肾毒素引起，在住院患者中是常见的，与ICU中高达50%的总死亡率有关，尽管发病率和死亡率很高，但没有专门的治疗方法，其病理生理学还不完全清楚。新的证据表明，抗氧化剂和氧化剂失衡(或氧化应激)导致细胞损伤、炎症和免疫反应参与了AKI的发病机制。因此，识别和了解调节氧化应激反应的分子效应物的功能和调节，以应对缺血和肾毒性损伤，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b-ZIP转录因子，对诱导几种抗氧化剂和细胞保护基因的表达至关重要)的遗传中断更容易引起IRI诱导的血管通透性和炎症反应。与野生型对照相比，NRF2缺陷(NRF2-/-)小鼠也更容易受到顺铂诱导的肾毒性AKI的影响。补充抗氧化剂显著改善了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活性是治疗缺血性和肾毒性AKI的潜在保护策略。由于Nrf2从细胞质到细胞核的转位在应激刺激后ARE介导的转录反应中起关键作用，我们认为，特定信号或控制Nrf2表达和激活的因素的扰动可以导致抗氧化酶表达水平降低，从而促进和/或增加对AKI的易感性。为了验证这些假说，我们提出了以下三个具体目标：1)阐明控制缺血再灌注反应中Nrf2激活的分子机制(上游信号)，2)确定在使用基因靶向Nrf2小鼠的AKI的发生和/或持续过程中，与常驻肾细胞相比，由白细胞渗透引起的氧化应激的贡献，以及3)确定使用药理学和遗传学方法促进Nrf2激活是否提供了对AKI的保护。我们从基因操作的小鼠模型和细胞培养研究中获得的总体结果应该会在AKI背后产生极其重要的见解，并可能对识别导致AKI易感性的效应器机制具有重要意义。该应用程序是在多学科团队方法中开发的，结合了转录生物学、体外和体内AKI模型以及炎症方面的优势。 公共卫生相关性：急性肾损伤是死亡率、发病率和医疗保健利用成本的主要原因。目前的建议利用细胞培养和基因操纵的小鼠模型，以及新的试剂来阐明Nrf2-Keap-ARE途径在小鼠AKI期间调节抗氧化剂和氧化剂失衡(氧化应激)的机制和治疗潜力。所提出的研究将为我们能够针对Nrf2-Keap1-ARE通路进行未来急性肾损伤的临床试验提供坚实的基础。