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 This hypothesis has been formulated based on published and unpublished research demonstrating that NFAs induce Nrf2, inhibit TLR4/NF?B signaling, protect the kidney against ischemia-reperfusion injury and prevent renal fibrosis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.
The research plan is relevant to public health because it proposes a novel pharmacological strategy that induces endogenous cytoprotective mechanisms and inhibits inflammation to prevent renal dysfunction in sickle cell disease. Renal dysfunction accounts for approximately 15% of all mortality associated with sickle cell disease, a condition that affects 100,000 Americans and 0.3 billion people worldwide. Thus, this proposal is significant to the NIH mission in that it seeks to apply fundamental knowledge to enhance health, lengthen life, and reduce illness and disability.
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