The role of ICAM-1 in endotoxin-induced acute renal failure.
The pathogenesis of acute renal failure (ARF) occurring during the course of sepsis is incompletely understood. Intercellular adhesion molecule-1 (ICAM-1) is a key cell adhesion molecule upregulated by LPS, which binds to the integrins CD11a/CD18 and CD11b/CD18 present on the surface of leukocytes. We hypothesized that ICAM-1 facilitates renal injury in LPS-induced ARF. To test this, three groups of mice (n = 8 per group) were injected intraperitoneally with 6 mg/kg LPS: 1) normal C57BL/6 mice, 2) mice with a targeted deficiency of ICAM-1 (ICAM-1(-/-)), and 3) mice expressing very low levels of CD18 (CD18-def). ICAM-1(-/-) mice were significantly resistant to LPS-mediated ARF, as opposed to CD18-def mice, which developed severe ARF, as did wild-type controls (48 h blood urea nitrogen 143 +/- 31.5, 70.8 +/- 24.4, and 185 +/- 16.6 mg/dl in wild-type, ICAM-1(-/-), and CD18-def mice, respectively, P < 0.05). At death, ICAM-1(-/-) mice had significantly less renal neutrophil infiltration than the other two groups, as well as less histological tubular injury. Depletion of neutrophils with mAb Gr-1 led to a profound exaggeration of tumor necrosis factor (TNF) release and high mortality, but neutrophil-depleted mice receiving 10-fold less LPS were protected against ARF despite TNF release similar to what is normally associated with LPS-induced ARF. LPS caused a significant increase in renal expression of chemokines; however, this increase was significantly exaggerated in CD18-def mice, which may account for their lack of protection. In conclusion, these data show that ICAM-1 plays a key role in LPS-induced ARF.
Section of Nephrology, University of Chicago, Chicago, Illinios, USA.
Xiaoyan
X
Wu
Rongqing
R
Guo
Ying
Y
Wang
Patrick N
PN
Cunningham
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D000818:Animals; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D004731:Endotoxins; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000473:pathology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018821:CD18 Antigens; D004731:Endotoxins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1