Protection against sickle cell disease nephropathy by nitrated fatty acids

硝化脂肪酸预防镰状细胞病肾病

• 批准号: 10405745
• 负责人: Dario A Vitturi
• 金额: $ 4.44万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-01-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405745
• 关键词: Address; Affect; Age; American; Antioxidants; Attenuated; Biological Availability; Bone Marrow Diseases; Chimera organism; Chronic; Development; Dose; Drug Kinetics; Endothelium; Event; Exposure to; Fatty Acids; Goals; Health; Heme; Hemolysis; Human; Hypertension; Inflammation; Injury to Kidney; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Life; Life Expectancy; Mediating; Mission; Modeling; Monitor; Morbidity - disease rate; Mus; Nitric Oxide; Nitrogen Dioxide; Oleic Acids; Organ; Oxidative Stress; Patients; Pharmacology; Prophylactic treatment; Public Health; Publishing; Recurrence; Regimen; Renal function; Reperfusion Injury; Research; Role; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Sodium Chloride; TLR4 gene; Testing; Time; Toxic effect; Transplantation; Tweens; United States National Institutes of Health; base; disability; drug clearance; effective therapy; inflammatory marker; injury prevention; innovation; kidney dysfunction; kidney fibrosis; mortality; novel; oral supplementation; phase I trial; prevent; renal damage; vascular inflammation

Renal dysfunction is strongly associated with decreased life expectancy in sickle cell disease (SCD). Kidneys in SCD are exposed to recurrent vaso-occlusive events due to intravascular erythrocyte sickling, as well as to heme toxicity as a result of chronic hemolysis. This scenario results in renal oxidative stress, vascu- lar inflammation and decreased nitric oxide bioavailability. Current therapies only address renal complications once they are established, thus the need for safe prophylactic treatments capable of attenuating nephropathy development is critical. The long-term goal is to generate effective therapies to alleviate the development of chronic complications that result in morbidity and mortality for SCD patients. Thus, the overall objective of this application is to define the potential of nitrated fatty acids (NFA) to prevent nephropathy development in a mu- rine model of SCD. The central hypothesis is that chronic administration of the NFA nitro-oleic acid (NO2-OA) beginning at an early age will attenuate the development of renal dysfunction via Nrf2-dependent increases in antioxidant defenses and inhibiting TLR4/NFB-mediated endothelial activation and vascular inflammation. This hypothesis has been formulated based on published and unpublished research demonstrating that NFAs induce Nrf2, inhibit TLR4/NFB signaling, protect the kidney against ischemia-reperfusion injury and prevent renal fibrosis and damage in a salt-overload hypertension model. The rationale for the proposed research is that once it is established that NO2-OA attenuates SCD nephropathy, translational treatment paradigms can be developed for the protection of the kidney and other affected organs. The central hypothesis will be tested by pursuing the following specific aims: 1) Establish an equivalent NO2-OA dosing regimen for control and SCD mice; 2) Define the effects of NO2-OA in SCD renal injury; and 3) Delineate the role of Nrf2 signaling in NO2- OA protection. Since altered renal function can affect drug clearance and availability, a pharmacokinetic analy- sis will be performed to establish an equivalent dosing regimen for control and SCD mice. Correlations be- tween renal function and pharmacokinetic parameters will be utilized for real-time dosing adjustments during NO2-OA administration studies. Under the second aim, control and SCD mice will be treated with NO2-OA or oleic acid (OA) starting at 4 weeks of age for 20 weeks. Renal injury and function, as well as oxidative stress and inflammation markers will be monitored. Aim 3 will establish the contribution of Nrf2-activation to NO2-OA protection by using chimeras generated by transplanting SCD bone marrow into Nrf2-null mice. Overall, the approach is innovative because it is based on the oral supplementation of an endogenously generated NFA capable of potentiating cellular defenses and attenuating inflammation, with no toxicity at the chosen dose and that has completed phase 1 trials in humans. The proposed research is significant because it is expected to pave the way for new Nrf2/NFB/TLR4-targeting strategies to be considered for the prevention of injury to kid- neys and other organs during the course of SCD.

肾功能不全与镰状细胞病（SCD）患者的预期寿命缩短密切相关。 SCD中的肾脏暴露于由于血管内红细胞镰状化引起的复发性血管闭塞事件， 以及由于慢性溶血导致的血红素毒性。这种情况会导致肾脏氧化应激，血管- 更大炎症和降低的一氧化氮生物利用度。目前的治疗仅针对肾脏并发症 因此，需要能够减轻肾病的安全预防性治疗， 发展至关重要。长期目标是产生有效的治疗方法，以缓解 导致SCD患者发病和死亡的慢性并发症。因此，本报告的总体目标 应用是确定硝化脂肪酸（NFA）预防肾病发展的潜力， SCD的rine模型。中心假设是长期给予NFA硝基油酸（NO2-OA） 从早期开始，通过Nrf 2依赖性增加， 抗氧化防御和抑制TLR 4/NF κ B介导的内皮活化和血管炎症。 这一假设是根据已发表和未发表的研究制定的，这些研究表明， 诱导Nrf 2，抑制TLR 4/NF κ B B信号通路，保护肾脏免受缺血再灌注损伤， 盐负荷高血压模型中的肾纤维化和损害。拟议研究的基本原理是 一旦确定NO2-OA减弱SCD肾病， 开发用于保护肾脏和其他受影响的器官。中心假设将通过以下方式进行检验： 追求以下具体目标：1）建立对照和SCD的等效NO2-OA给药方案 小鼠; 2）确定NO2-OA在SCD肾损伤中的作用;和3）描述Nrf 2信号在NO2-OA中的作用。 OA保护。由于肾功能改变可影响药物清除率和可用性，因此药代动力学分析 进行SIS以建立对照和SCD小鼠等效给药方案。相关性是- 肾功能和药代动力学参数之间的差异将用于实时剂量调整， NO2-OA给药研究。在第二个目的下，对照和SCD小鼠将用NO2-OA或NO2-OA-A处理。 油酸（OA），从4周龄开始，持续20周。肾损伤和功能，以及氧化应激 并监测炎症标志物。目的3将确定Nrf 2-活化对NO2-OA的贡献 通过使用通过将SCD骨髓移植到Nrf 2缺失小鼠中产生的嵌合体来保护。总体看 这种方法是创新的，因为它是基于口服补充内源性产生的NFA 能够增强细胞防御和减轻炎症，在所选剂量下没有毒性， 已经完成了第一阶段的人体试验这项研究意义重大，因为它有望 为新的Nrf 2/NF κ B B/TLR 4靶向策略铺平道路，以预防儿童损伤， 在SCD的过程中，神经和其他器官。

项目成果

The Chemical Basis of Thiol Addition to Nitro-conjugated Linoleic Acid, a Protective Cell-signaling Lipid.

硝基共轭亚油酸（一种保护性细胞信号脂质）中硫醇加成的化学基础。

• DOI: 10.1074/jbc.m116.756288
• 发表时间: 2017
• 期刊: The Journal of biological chemistry
• 作者: Turell,Lucía;Vitturi,DaríoA;Coitiño,ELaura;Lebrato,Lourdes;Möller,MatíasN;Sagasti,Camila;Salvatore,SoniaR;Woodcock,StevenR;Alvarez,Beatriz;Schopfer,FranciscoJ
• 通讯作者: Schopfer,FranciscoJ