Mesangial cell (MC) hyperplasia and accumulation of extracellular matrix are the predominant features of HIV-associated nephropathy (HIVAN). Since mice transgenic for HIV-1 genes show renal lesions mimicking HIVAN, we studied the effect of HIV-1 gpl60 protein on cultured murine MC (MMC) proliferation and apoptosis. HIV-1 gp160 protein stimulated (p < 0.001) MMC proliferation when compared with control MMCs. This effect of gpl60 protein peaked at a concentration of 0.01 μg/ml. MMCs treated with a higher concentration of gpl60 protein (0.1 μg/ml) or for a prolonged period of time (72 h) showed apoptosis rather than cell proliferation. These studies were further confirmed by DNA fragmentation and end labeling assays. Gp160 also enhanced apoptosis in human MCs. Tumor necrosis factor (TNF)-α enhanced (p < 0.001) MMC apoptosis, and anti-TNF-α antibodies inhibited gp160-induced MMC apoptosis. In addition, gp160 protein attenuated MMC expression of Bcl-2 mRNA expression. These results suggest that gp160-induced apoptosis may be affected in part by the release of TNF-α and associated with attenuated mRNA expression of Bcl-2 by MMCs.