Previous studies have shown that both iron deficiency/overload may adversely affect the clinical outcome of AIDS. We have recently found significant iron deposits in the kidney of HIV-infected children and HIV- transgenic (Tg) rats with renal disease and thrombotic microangiopathy (TMA). VE is a powerful antioxidant, and previous studies have shown that VE supplementation can ameliorate iron toxicity in rodents and children. However, up to date, the role that VE may play in ameliorating the cytotoxic effects of iron accumulation in the context of HIV-infection has not been explored before. We hypothesize that VE supplementation decreases the renal accumulation of iron and improves the histological and clinical outcome of the TMA lesions and renal disease in HIV-Tg rats.
Two specific aims will be studied:
Aim 1) To determine whether VE deprivation/supplementation modulates the clinical/histological outcome of the TMA lesions and renal disease in HIV-Tg rats. Here, we will define whether VE deficiency / supplementationinduces, prevents the development of renal vascular TMA lesions and renal disease in HIV-Tg rats subjected to low, normal, and high iron intakes.
Aim 2) To define the molecular pathways involved in the pathogenesis of iron accumulation and induction of TMA lesions in renal microvessels dissected from HIV-Tg rats, using a genome-wide profiling approach and Affymetrix U34 arrays. Here, our experience will be applied to identify the changes induced by iron/VE, throughout the development of renal TMA lesions and microvascular endothelial injury using a time-series to identify pathways involved in the development of these lesions and leading to the accumulation of iron in the kidney. Positive findings will be validated in renal sections from HIV-Tg rats and HIV-infected children with and without renal disease, by RT-PCR, in situ hybridization, immunohistochemistry, Northern and Western blots. These experiments will provide fundamental new knowledge to understand the pathogenesis of renal iron accumulation in HIV-infected children; establish a new animal model system to test the role of VE in this process, and provide relevant pre-clinical data in favor or against the use of VE as a CAM therapy to prevent the development of iron toxicity in HIV-infected children. The proposed studies should have a substantial impact on the goals of the National Center for Complementary and Alternative Medicine and NIH, according to the program announcement PA-02-124. ? ?
