Protective effects of specific platelet-activating factor receptor antagonists in experimental glomerulonephritis

The present study was undertaken to evaluate the hypothesis that enhanced production of platelet-activating factor (PAF) contributes to the renal hemodynamic alterations and impaired glomerular permselectivity that characterize the heterologous phase of nephrotoxic serum nephritis. Intravenous administration of nephrotoxic gamma globulin to normal rats led to a rapid decline in glomerular filtration rate within 60 min from 1.08 ± 0.08 to 0.45 ± 0.12 ml/min/100 g b.wt., P < .001, and in effective renal plasma flow rate from 2.56 ± 0.15 to 1.35 ± 0.21 ml/min/100 g b.wt., P < .02. Concomitantly, the fractional excretion of protein rose from 3.4 ± 0.6 x 10^-5 to 11.6 ± 2.3 x 10^-5, P < .03. Pretreatment with the specific PAF receptor antagonists WEB 2086 or WEB 2170 significantly ameliorated the impairment in glomerular filtration rate and in effective renal plasma flow rate induced by nephrotoxic globulin. Filtration rate declined by 0.63 ± 0.12 ml/min/100 g b.wt. 60 min after administration of nephrotoxic globulin, but fell only 0.30 ± 0.14 ml/min/100 g b.wt. in rats pretreated with WEB 2086, P < .05 and 0.34 ± 0.11 ml/min/100 g b.wt. in rats pretreated with WEB 2170, P < .01. The decline in effective renal plasma flow rate 60 min after administration of nephrotoxic globulin was 1.21 ± 0.30 ml/min/100 g b.wt., but only 0.86 ± 0.23 ml/min/100 g b.wt. in rats pretreated with WEB 2086, NS, and 0.52 ± 0.21 ml/min/100 g b.wt. in rats pretreated with WEB 2170, P < .003. The rise in fractional excretion of protein induced by nephrotoxic globulin was also ameliorated in animals pretrated with either PAF receptor antagonist. Administration of nephrotoxic globulin was not associated with altered glomerular size selectivity as assessed by the fractional clearance of neutral dextrans, suggesting that the observed defect in glomerular permselectivity was due to altered glomerular charge selectivity. In rats pretreated with a PAF receptor antagonist, the fractional excretion of protein failed to increase and fractional dextran clearances were unchanged, suggesting that PAF contributes to impaired glomerular charge selectivity in this model. Our data suggest that PAF is one of the mediators of the glomerular hemodynamic and permselective responses early in the heterologous phase of nephrotoxic serum nephritis.