Involvement of tumor necrosis factor and platelet-activating factor in the pathogenesis of experimental nephrosis in rats.
BACKGROUND
The experimental nephrosis induced in rats by adriamycin (ADR) or puromycin aminonucleoside (PA) provide a useful model to study the participation of inflammatory mediators in the pathogenesis of proteinuria.


METHODS
We have measured tumor necrosis factor (TNF) and platelet-activating factor (PAF) production by glomeruli of rats with nephrosis, as well as the effect of treatment with the PAF antagonist, BN52021. We have also evaluated the in vitro effects of ADR, PA, and PAF on TNF and PAF production, cell viability, and protein synthesis in glomerular mesangial cells and glomerular epithelial cells (GEC) in culture.


RESULTS
In ADR nephrosis, the greatest production of PAF was on day 14, preceding maximal proteinuria, whereas the highest levels of TNF where observed on day 21 after ADR injection, the moment at which proteinuria reached maximal levels. In PA nephrosis, glomerular PAF production peaked twice (days 1 and 15), before and after maximal proteinuria (day 11), whereas TNF production peaked from days 2 to 11, and slowly declined until day 21. In both models, treatment with BN52021 induced a striking decrease in proteinuria, as well as a diminution in glomerular TNF and PAF production. Both ADR and PA induced TNF and PAF production in whole glomeruli, glomerular mesangial cells, and GEC in culture. As shown by a 51Cr release assay, ADR and PA were toxic to GEC. This effect was inhibited by PAF antagonists and by anti-TNF antibodies. Whereas TNF was moderately toxic to GEC, PAF had no effect on 51Cr release. TNF toxicity was abolished by anti-TNF antibodies and largely diminished by PAF antagonists.


CONCLUSIONS
TNF and PAF may participate in the induction of GEC damage and the development of proteinuria in two experimental models of nephrosis in rats.
Gómez-Chiarri
M
M
Renal Unit, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Ortíz
A
A
Lerma
J L
JL
López-Armada
M J
MJ
Mampaso
F
F
González
E
E
Egido
J
J
D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D004224:Diterpenes; D004317:Doxorubicin; D005260:Female; D046934:Ginkgolides; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D009401:Nephrosis / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D010972:Platelet Activating Factor / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects*; D011507:Proteinuria / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D011692:Puromycin Aminonucleoside; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; C039351:platelet activating factor receptor; D011692:Puromycin Aminonucleoside; D004317:Doxorubicin; C045856:ginkgolide B