Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that plays a central role in inflammation. Glomerular levels of TNF-alpha are elevated in human and experimental glomerulonephritis. Glomerular cells produce and respond to TNF-alpha. One of the mechanisms by which these cells respond to TNF-alpha is through generation of reactive oxygen species. In this study, the effect of TNF-alpha on albumin permeability (P (albumin)) of isolated rat glomeruli and the possible mechanism of this effect were examined. Isolated rat glomeruli were incubated with TNF-alpha (0.4 ng/ml), TNF-alpha with anti-TNF-alpha antibodies, and TNF-alpha with the reactive oxygen species scavengers superoxide dismutase, catalase, DMSO, or dimethylthiourea for 12 min at 37 degrees C, and P (albumin) was calculated. TNF-alpha increased P (albumin) of isolated glomeruli compared with control (0.70+/-0.02, n= 25 versus 0.00+/-0.05, n= 26), and this effect was abrogated by anti-TNF-alpha antibodies (-0.18+/-0.05, n= 23). Superoxide dismutase abolished the increase in P (albumin)(-0.04+/-0.11, n= 23), whereas catalase (0.73+/-0.08, n= 30), DMSO (0.64+/-0.03, n= 10), or dimethylthiourea (0.51+/-0.08, n= 10) did not alter the effect of TNF-alpha. These results indicate that TNF-alpha increased P (albumin+)++ of isolated glomeruli and that the mediator of the increased P (albumin) is superoxide. It is concluded that TNF-alpha derived from glomerular or extraglomerular sources can increase glomerular P (albumin) through generation of superoxide and may lead to proteinuria.