IMPROVED SURVIVAL AND AMELIORATION OF NEPHROTOXIC NEPHRITIS IN INTERCELLULAR-ADHESION MOLECULE-1 KNOCKOUT MICE

Intercellular adhesion molecule-1 (ICAM-1) expression is upregulated i n nephrotoxic nephritis, a model of human rapidly progressive glomerul onephritis. To evaluate the pathogenetic relevance of ICAM-1 in this m odel, nephrotoxic nephritis was induced in ICAM-1 knockout mice and ge netic controls. Mice were preimmunized with rabbit IgG in complete Fre und's adjuvant. Seven days later they received rabbit anti-mouse glome rular basement membrane IgG. The early humoral immune responses (level s of circulating mouse anti-rabbit IgG, glomerular deposition of rabbi t and mouse IgG and mouse C3c) were not altered in ICAM-1 knockout mic e. During 28 d of follow-up, 3 of 19 control nephritic mice and 0 of 1 6 ICAM-1 knockout mice died. Proteinuria was high in nephritic control mice (means 10 to 12 mg/24 h at all time points investigated) and sig nificantly reduced in nephritic ICAM-1 knockout mice (means <4.4 mg). Mean serum creatinine rose from 29 mu mol/L at day -7 to 48 mu mol/L ( day 28) in nephritic control mice. This increase in serum creatinine w as significantly lower in ICAM-1 knockout mice: 27 (day -7) and 36 mu mol/L (day 28). Histologic analysis at day 28 revealed that ICAM-1 def iciency in nephrotoxic nephritis mice led to significantly reduced glo merular crescent formation (2 +/- 3% in ICAM-1 knockout mice ver sus 1 3 +/- 8% in nephritic controls) and tubulointerstitial injury (score 0 .4 +/- 0.4 versus 2.0 +/- 1.1). By immunohistochemistry, ICAM-1 defici ency in nephritic mice led to significantly reduced (peri-)glomerular and/or interstitial macrophage influx, alpha-smooth muscle actin expre ssion, and type IV collagen accumulation. These data indicate that ICA M-1 is a central mediator of glomerular and tubulointerstitial injury in murine nephrotoxic nephritis.