Hydroxyl radical mediation of immune renal injury by desferrioxamine.
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 antiGBM-GN control = 271.5 +/- 92.2 mg, P less than 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/10(6) cells, mean +/- SEM, ISN/DFX = 8 +/- 2 compared with ISN = 191 +/- 22, P less than 0.01] while production of O2- was not affected [nM O2-/hr/10(6) cells, mean +/- SEM, ISN/DFX = 29.1 +/- 4.3 compared with ISN = 32.6 +/- 2.5, P greater than 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.
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D001485:Basement Membrane / Q000276:immunology; D003676:Deferoxamine / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005921:Glomerulonephritis / Q000139:chemically induced / Q000276:immunology; D006878:Hydroxides / Q000494:pharmacology*; D017665:Hydroxyl Radical; D007678:Kidney Glomerulus / Q000276:immunology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D011507:Proteinuria / Q000517:prevention & control; D011817:Rabbits; D012756:Sheep / Q000276:immunology; D013481:Superoxides / Q000378:metabolism
D000906:Antibodies; D006878:Hydroxides; D013481:Superoxides; D017665:Hydroxyl Radical; D003676:Deferoxamine