We wish to characterize the mechanisms for responsible for focal segmental glomerulosclerosis (FSGS) and use these findings to devise more effective therapy; we are particularly interested in HIV-associated FSGS. We have hypothesized that HIV accessory proteins (Vpr, Vpu, and Vif) mediate renal injury, leading to the histologic pattern of focal segmental glomerulosclerosis. We have established transgenic lines in with the endothelin-1 promoter (ET) drives Vpu or Vif. ET-vpu mice have a lung phenotype, in which the bronchioles and arterioles have perivascular cuffing (composed predominantly of macrophages) and macrophage pneumonitis characterized by macrophages within the alveoli. Endothelial cells, the presumed site of transgene expression, show activation markers, including increased expression of ICAM-1. Endothelial cells have been shown to be infected with HIV-1 in vitro and in vivo. Thus these findings suggest that the accessory protein Vpu may activate endothelial cells to promote leukocyte entry into tissues. We have collected blood and prepared immortalized B cell lines as a source of DNA from approximately 123 African-American patients with FSGS and a control group 193 African Americans infected with HIV but without renal disease, with the help of collaborators from eight medical centers around the country. We have initiated candidate gene analysis and have examined renin, angiogensin converting enzyme, kallikrein, and the Duffy antigen without finding a disease linkage. We plan to begin a random genome scan within the next year
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