TNF-α increases albumin permeability of isolated rat glomeruli through the generation of superoxide

Abstract

Tumor necrosis factor-α (TNF-α) is a cytokine that plays a central role in inflammation. Glomerular levels of TNF-α are elevated in human and experimental glomerulonephritis. Glomerular cells produce and respond to TNF- α. One of the mechanisms by which these cells respond to TNF-α is through generation of reactive oxygen species. In this study, the effect of TNF-α 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-α (0.4 ng/ml), TNF-α with anti-TNF-α antibodies, and TNF-α with the reactive oxygen species scavengers superoxide dismutase, catalase, DMSO, or dimethylthiourea for 12 min at 37°C, and P(albumin) was calculated. TNF- α 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-α 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-α. These results indicate that TNF-α increased P(albumin) of isolated glomeruli and that the mediator of the increased P(albumin) is superoxide. It is concluded that TNF-α derived from glomerular or extraglomerular sources can increase glomerular P(albumin) through generation of superoxide and may lead to proteinuria.