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To determine the specific role of Nef in the pathogenesis of HIV-associated nephropathy.Podocytes are highly differentiated non-dividing cells in the normal glomerulus, however, they undergo dedifferentiation and acquire a proliferative phenotype in HIVAN patients, in HIV-transgenic mice and if infected by HIV-1 in vitro. These changes are accompanied by loss of the maturation markers synaptopodin and WT1, and expression of the proliferation marker Ki-67. Previously, we mapped the gene responsible for these changes in vitro to HIV-1 Nef. To determine the role of Nef in vivo, we developed a transgenic mouse model in which Nef was exclusively expressed in podocytes.Transgenic mice were generated using a construct in which Nef expression was blocked by a floxed lacZ intervening gene. When crossed with another transgenic mice expressing Cre under the Podocin promoter (a podocyte specific gene), the intervening lacZ gene was removed activating the expression of Nef in podocytes. The in vivo expression profiles of the Nef, the proliferation marker Ki-67, the differentiation markers synaptopodin and WT1, and phospho-Stat3, were determined by immunohistochemistry.Podocyte-specific expression of Nef induced loss of synaptopodin and WT1, and expression of Ki-67 in podocytes. Furthermore, Nef activated expression of phospho-Stat3, one of the downstream signaling pathways for cell proliferation.We conclude that Nef induces the early molecular changes in podocytes that are essential for the dedifferentiation and proliferation of podocytes in HIVAN pathogenesis. These data provide the first clear molecular evidence that Nef alters the podocyte phenotype in vivo.