A role for P selectin in complement-independent neutrophil-mediated glomerular injury

Kidney Int. 1994 Jul;46(1):79-88. doi: 10.1038/ki.1994.246.

Abstract

Neutrophil recruitment and lung injury following complement activation have been demonstrated to be dependent on endothelial expression of P selectin. In anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM GN) in mice, acute glomerular injury results from complement-independent neutrophil accumulation. The signals for neutrophil recruitment in this model are unknown. Expression of P selectin on glomerular endothelium was demonstrated within 30 minutes of administration of anti-GBM antibody to C57/BL10 mice. This was associated with rapid accumulation of neutrophils in glomeruli which peaked at one hour (6.2 +/- 0.5 neutrophils per glomerular cross section [neut/gcs], normal 0.34 +/- 0.06 neut/gcs, P < 0.01) and significant proteinuria after 16 hours (3.6 +/- 0.5 mg/16 hr, control 0.62 +/- 0.13 mg/16 hr, P < 0.01). Complement depletion with cobra venom factor, which reduced serum C3 levels to less than 5% of normal, did not alter expression of P selectin, reduce glomerular neutrophil accumulation (6.7 +/- 0.8 neut/gcs) or proteinuria (3.7 +/- 0.5 mg/16 hr). Platelet depletion also failed to alter glomerular expression of P selectin, neutrophil accumulation or the development of proteinuria. Mice were treated with an affinity purified anti-human P selectin antibody, which cross reacted with mouse P selectin and blocked P selectin-dependent binding of thrombin-activated mouse platelets to HL60 cells and did not bind to mouse neutrophils. Treatment, one hour prior to the administration of anti-GBM antibody, markedly inhibited glomerular neutrophil accumulation (0.94 +/- 0.12 neut/gcs) and prevented proteinuria (1.0 +/- 0.2 mg/16 hr), and did not alter binding of anti-GBM globulin in the kidney. These data strongly suggest that the rapid up-regulation of P selectin expression in glomeruli following binding of anti-GBM antibody is an essential signal for neutrophil recruitment in this complement independent model of glomerular injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basement Membrane / immunology
  • Blood Platelets / immunology
  • Complement C3 / deficiency
  • Complement C3 / immunology*
  • Glomerulonephritis / immunology*
  • Glomerulonephritis / pathology
  • Kidney Glomerulus / immunology*
  • Kidney Glomerulus / pathology
  • Leukocyte Count
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / immunology
  • P-Selectin
  • Platelet Membrane Glycoproteins / immunology*
  • Up-Regulation

Substances

  • Complement C3
  • P-Selectin
  • Platelet Membrane Glycoproteins