Protection against sickle cell disease nephropathy by nitrated fatty acids

肾功能不全与镰状细胞病(SCD)患者的预期寿命降低密切相关。 SCD患者的肾脏暴露于血管内红细胞病变引起的反复血管闭塞事件，AS 以及由于慢性溶血而产生的血红素毒性。这种情况会导致肾脏氧化应激，血管紧张素转换酶 Lar炎症和一氧化氮生物利用度降低。目前的治疗只针对肾脏并发症。 一旦它们被确定，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来缓解糖尿病的发展。 导致SCD患者发病率和死亡率的慢性并发症。因此，这一行动的总体目标是 应用是确定硝基脂肪酸(NFA)在预防小鼠肾病发展中的潜力。 SCD的RINE模型。中心假设是长期服用NFA硝基-油酸(NO2-OA) 从小开始将通过Nrf2依赖的增加来减缓肾功能障碍的发展。 抗氧化防御和抑制TLR4/NFB介导的内皮激活和血管炎症。 这一假说是根据已发表和未发表的研究提出的，该研究表明，NFA 诱导NRF2，抑制TLR4/NFB信号转导，保护肾脏免受缺血再灌注损伤 盐负荷高血压模型中的肾脏纤维化和损害。建议进行这项研究的理由是 一旦确定NO2-OA可以减轻SCD肾病，转化性治疗范例可以 为保护肾脏和其他受影响的器官而开发的。核心假设将通过以下方式进行检验 追求以下具体目标：1)为对照和SCD建立等效的NO2-OA给药方案 2)明确NO2-OA在SCD肾损伤中的作用；3)阐明Nrf2信号在NO2-OA中的作用。 办公自动化保护。由于肾功能改变会影响药物的清除量和利用度，因此药物动力学分析-- 将进行SIS，为对照组和SCD小鼠建立同等剂量的给药方案。相关性是- 肾功能与药代动力学参数之间的关系将被用于实时剂量调整 第2名--办公自动化管理研究。在第二个目标下，对照组和SCD小鼠将接受NO2-OA或 油酸(OA)从4周龄开始，持续20周。肾脏损伤和功能，以及氧化应激 并将监测炎症标志物。目标3将确定Nrf2激活对NO2-OA的贡献 通过将SCD骨髓移植到Nrf2缺失小鼠产生的嵌合体来保护。总体而言， 方法是创新的，因为它是基于内源性NFA的口服补充 能够增强细胞防御和减轻炎症，在选定的剂量和 它已经完成了第一阶段的人体试验。这项拟议的研究意义重大，因为预计它将 为新的NRF2/NFB/TLR4-为预防儿童受伤而考虑的靶向策略铺平道路- Neys和其他器官在SCD过程中的作用。

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 This hypothesis has been formulated based on published and unpublished research demonstrating that NFAs induce Nrf2, inhibit TLR4/NFB signaling, protect the kidney against ischemia-reperfusion injury and prevent renal fibrosis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.