Involvement of tumor necrosis factor and platelet-activating factor in the pathogenesis of experimental nephrosis in rats

• Published in: Laboratory investigation Vol. 70; no. 4; pp. 449 - 459
• Main Authors: GOMEZ-CHIARRI, M, ORTIZ, A, LERMA, J. L, LOPEZ-ARMADA, M. J, MAMPASO, F, GONZALEZ, E, EGIDO, J
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing 01.04.1994
• Subjects: Animals; Biological and medical sciences; Cell Death; Cells, Cultured; Diterpenes; Doxorubicin; Female; Ginkgolides; Kidney Glomerulus - cytology; Kidney Glomerulus - metabolism; Lactones - pharmacology; Medical sciences; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Nephrosis - chemically induced; Nephrosis - pathology; Nephrosis - physiopathology; Platelet Activating Factor - physiology; Platelet Membrane Glycoproteins - drug effects; Proteinuria - chemically induced; Proteinuria - pathology; Proteinuria - physiopathology; Puromycin Aminonucleoside; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Tubulopathies; Tumor Necrosis Factor-alpha - physiology; Animal model; Urinary system disease; Rat; Pathogenesis; Cytokine; Rodentia; Tubulopathy; Phospholipid; Renal disease; Cytotoxicity; In vitro; Platelet activating factor; Vertebrata; Experimental disease; Mammalia; Tumor necrosis factor; Protein synthesis; Osmotic nephrosis; Viability; Proteinuria
• ISSN: 0023-6837; 1530-0307

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. 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. 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. TNF and PAF may participate in the induction of GEC damage and the development of proteinuria in two experimental models of nephrosis in rats.