Improved survival and amelioration of nephrotoxic nephritis in intercellular adhesion molecule-1 knockout mice.
Intercellular adhesion molecule-1 (ICAM-1) expression is upregulated in nephrotoxic nephritis, a model of human rapidly progressive glomerulonephritis. To evaluate the pathogenetic relevance of ICAM-1 in this model, nephrotoxic nephritis was induced in ICAM-1 knockout mice and genetic controls. Mice were preimmunized with rabbit IgG in complete Freund's adjuvant. Seven days later they received rabbit anti-mouse glomerular basement membrane IgG. The early humoral immune responses (levels of circulating mouse anti-rabbit IgG, glomerular deposition of rabbit and mouse IgG and mouse C3c) were not altered in ICAM-1 knockout mice. During 28 d of follow-up, 3 of 19 control nephritic mice and 0 of 16 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 significantly reduced in nephritic ICAM-1 knockout mice (means <4.4 mg). Mean serum creatinine rose from 29 micromol/L at day -7 to 48 micromol/L (day 28) in nephritic control mice. This increase in serum creatinine was significantly lower in ICAM-1 knockout mice: 27 (day -7) and 36 micromol/L (day 28). Histologic analysis at day 28 revealed that ICAM-1 deficiency in nephrotoxic nephritis mice led to significantly reduced glomerular crescent formation (2+/-3% in ICAM-1 knockout mice versus 13+/-8% in nephritic controls) and tubulointerstitial injury (score 0.4+/-0.4 versus 2.0+/-1.1). By immunohistochemistry, ICAM-1 deficiency in nephritic mice led to significantly reduced (peri-)glomerular and/or interstitial macrophage influx, alpha-smooth muscle actin expression, and type IV collagen accumulation. These data indicate that ICAM-1 is a central mediator of glomerular and tubulointerstitial injury in murine nephrotoxic nephritis.
Janssen
U
U
Division of Nephrology, Medizinische Hochschule, Hannover, Germany.
Ostendorf
T
T
Gaertner
S
S
Eitner
F
F
Hedrich
H J
HJ
Assmann
K J
KJ
Floege
J
J
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000032:analysis*; D001485:Basement Membrane / Q000276:immunology; D003094:Collagen / Q000032:analysis; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000737:chemistry; D005260:Female; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007074:Immunoglobulin G / Q000032:analysis*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007668:Kidney / Q000473:pathology; D007677:Kidney Function Tests; D051379:Mice; D018345:Mice, Knockout; D011507:Proteinuria / Q000276:immunology; D011817:Rabbits; D012016:Reference Values; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D015854:Up-Regulation
D000888:Antibodies, Anti-Idiotypic; D007074:Immunoglobulin G; D018799:Intercellular Adhesion Molecule-1; D003094:Collagen