Hydroxyl radical mediation of immune renal injury by desferrioxamine

Abstract

The acute phase of glomerular injury in a model of antiglomerular basement membrane, antibody-induced glomerulonephritis (antiGBM-GN) in rabbits was shown to be neutrophil-dependent using nitrogen mustard depletion studies. Administration of desferrioxamine (DFX) prevented the development of proteinuria in this model of renal injury [24 hr protein excretion (mean ± SEM): antiGBM-GN/DFX = 16.2 ± 2.9 mg compared with antiGMB-GN control = 271.5 ± 92.2 mg, P < 0.01]. Antibody binding levels, glomerular filtration rates, circulating complement and neutrophil counts, glomerular C3 deposition, and neutrophil infiltration did not differ between DFX treated and antiGBM-GN groups. In vitro assay systems to assess oxygen radical production [superoxide anion (O2-) and hydroxyl radical (OH.)] by neutrophils activated via the interaction of antiGBM antibody, GBM and complement were established. In these assays, DFX inhibited OH. production by immunologically-stimulated neutrophils (ISN) [nM diphenol/hr/106 cells, mean ± SEM, ISN/DFX = 8 ± 2 compared with ISN = 191 ± 22, P < 0.01] while production of O2- was not affected [nM O2-/hr/106 cells, mean ± SEM, ISN/DFX = 29.1 ± 4.3 compared with ISN = 32.6 ± 2.5, P > 0.05]. These studies demonstrate that the iron chelator desferrioxamine can prevent neutrophil-dependent immune renal injury by interfering with neutrophil function. Treatment with the hydroxyl radical scavenger dimethylthiourea also significantly attenuated renal injury in antiGBM-GN. Together, the in vivo and in vitro data strongly suggest that neutrophil-dependent immunological renal injury is mediated via hydroxyl radical production by activated neutrophils within glomeruli.