Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury.
Studies in the rat have pointed to a role for intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of acute tubular necrosis. These studies used antibodies, which may have nonspecific effects. We report that renal ICAM-1 mRNA levels and systemic levels of the cytokines IL-1 and TNF-alpha increase 1 h after ischemia/ reperfusion in the mouse. We sought direct proof for a critical role for ICAM-1 in the pathophysiology of ischemic renal failure using mutant mice genetically deficient in ICAM-1. ICAM-1 is undetectable in mutant mice in contrast with normal mice, in which ICAM-1 is prominent in the endothelium of the vasa recta. Mutant mice are protected from acute renal ischemic injury as judged by serum creatinine, renal histology, and animal survival . Renal leukocyte infiltration, quantitated morphologically and by measuring tissue myeloperoxidase, was markedly less in ICAM-1-deficient than control mice. To evaluate whether prevention of neutrophil infiltration could be responsible for the protection observed in the mutant mice, we treated normal mice with antineutrophil serum to reduce absolute neutrophil counts to < 100 cells/mm3. These neutrophil-depleted animals were protected against ischemic renal failure. Anti-1CAm-1 antibody protected normal mice against renal ischemic injury but did not provide additional protection to neutrophil-depleted animals. Thus, ICAM-1 is a key mediator of ischemic acute renal failure likely acting via potentiation of neutrophilendothelial interactions.
Kelly
K J
KJ
Medical and Pathology Services, Massachusetts General Hospital, Boston 02114, USA.
Williams
W W
WW
Colvin
R B
RB
Meehan
S M
SM
Springer
T A
TA
Gutierrez-Ramos
J C
JC
Bonventre
J V
JV
D000818:Animals; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000098:blood supply*; D007674:Kidney Diseases / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism
D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase