TNF-alpha increases albumin permeability of isolated rat glomeruli through the generation of superoxide.
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.
McCarthy
E T
ET
Department of Medicine, Medical College of Wisconsin, Milwaukee 53226, USA.
Sharma
R
R
Sharma
M
M
Li
J Z
JZ
Ge
X L
XL
Dileepan
K N
KN
Savin
V J
VJ
D000287:Administration, Topical; D000418:Albumins / Q000187:drug effects / Q000493:pharmacokinetics*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000418:Albumins; D000893:Anti-Inflammatory Agents; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C038983:1,3-dimethylthiourea; D002374:Catalase; D013482:Superoxide Dismutase; D013890:Thiourea; D004121:Dimethyl Sulfoxide