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（由申请人提供）：由缺血再灌注（IR）或肾毒素引起的急性肾损伤（阿基）在住院患者中很常见，并且与ICU中高达50%的总死亡率相关。尽管发病率和死亡率高，但没有特异性治疗，病理生理学也不完全清楚。新出现的证据表明，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阿基的发病机制。因此，识别和理解响应于缺血和肾毒性损伤而调节氧化应激的分子效应物的功能和调节可能导致阿基的新治疗机会。在初步研究中，我们发现，与野生型（Nrf 2 +/+）小鼠相比，Nrf 2（一种对诱导几种抗氧化剂和细胞保护基因表达至关重要的b-ZIP转录因子）遗传破坏的小鼠对IR诱导的血管通透性和炎症反应更敏感。与野生型对照组相比，Nrf 2缺陷型（Nrf 2-/-）小鼠也更容易发生顺铂诱导的肾毒性阿基。抗氧化剂补充显著改善了Nrf 2-/-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Nrf 2在阿基中具有保护作用，并且Nrf 2活性的增强是缺血性和肾毒性阿基的潜在保护策略。由于Nrf 2从细胞质到细胞核的易位对于应激刺激后ARE介导的转录应答至关重要，我们提出，特定信号传导或控制Nrf 2表达和活化的因子的扰动可导致抗氧化酶表达水平降低，从而有助于和/或增强阿基发展的易变性。为了验证这些假设，我们提出了以下三个具体目标：1）阐明分子机制（上游信号），其控制响应于缺血再灌注的Nrf 2的活化，2）使用基因靶向的Nrf 2小鼠，定义与驻留的肾细胞相比，由浸润的白细胞引起的氧化应激在阿基的发展和/或持续中的贡献，和3）确定使用药理学和遗传学方法加强Nrf 2活化是否赋予针对阿基的保护。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研究结果应该产生对阿基的极其重要的见解，并可能对确定导致阿基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的团队方法相结合的优势，在转录生物学，体外和体内阿基模型，炎症。 公共卫生相关性：急性肾损伤是死亡率、发病率和医疗保健使用成本的主要原因。目前的提议利用细胞培养和遗传操作的小鼠模型以及新型试剂来阐明Nrf 2-Keap-ARE途径的机制和治疗潜力，该途径在小鼠阿基期间调节抗氧化剂和氧化剂失衡（氧化应激）。拟议的研究将为我们在急性肾损伤的未来临床试验中靶向Nrf 2-Keap 1-ARE通路提供坚实的基础。