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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AT002278-01A2
Application #
7004628
Study Section
Special Emphasis Panel (ZRG1-AARR-A (91))
Program Officer
Caldwell, Sheila
Project Start
2005-09-30
Project End
2007-09-29
Budget Start
2005-09-30
Budget End
2006-09-29
Support Year
1
Fiscal Year
2005
Total Cost
$207,500
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Debebe, Zufan; Ammosova, Tatyana; Breuer, Denitra et al. (2011) Iron chelators of the di-2-pyridylketone thiosemicarbazone and 2-benzoylpyridine thiosemicarbazone series inhibit HIV-1 transcription: identification of novel cellular targets--iron, cyclin-dependent kinase (CDK) 2, and CDK9. Mol Pharmacol 79:185-96
Soler-García, Angel A; Johnson, Douglas; Hathout, Yetrib et al. (2009) Iron-related proteins: candidate urine biomarkers in childhood HIV-associated renal diseases. Clin J Am Soc Nephrol 4:763-71
Ray, Patricio E (2009) Taking a hard look at the pathogenesis of childhood HIV-associated nephropathy. Pediatr Nephrol 24:2109-19
Jerebtsova, Marina; Ye, Xuehai; Ray, Patricio E (2009) A simple technique to establish a long-term adenovirus mediated gene transfer to the heart of newborn mice. Cardiovasc Hematol Disord Drug Targets 9:136-40
Soler-García, Angel A; Rakhmanina, Natella Y; Mattison, Parnell C et al. (2009) A urinary biomarker profile for children with HIV-associated renal diseases. Kidney Int 76:207-14
McCulloch, Mignon I; Ray, Patricio E (2008) Kidney disease in HIV-positive children. Semin Nephrol 28:585-94