Antisense oligonucleotides for ICAM-1 attenuate reperfusion injury and renal failure in the rat.
The leukocyte adhesion molecule ICAM-1 is implicated in ischemic renal reperfusion injury. We tested the utility of an ICAM-1 antisense oligodeoxyribonucleotide (ODN) with lipofectin, six hours prior to 30 minutes of bilateral renal ischemia in the rat. We measured ICAM-1 expression by immunohistochemistry and Western blot. Our antisense ODN showed a specific ICAM-1 surface expression inhibition in vitro. We then assessed ICAM-1 expression, leukocyte infiltration, serum creatinine, serum urea concentration, and renal histology in rats subjected to renal ischemia and controls. Serum creatinine and urea concentrations 12 and 24 hours post-ischemia were increased in saline treated and reverse ODN treated rats, compared to antisense ODN treated or sham operated rats (P < 0.05). Western blotting showed decreased ICAM-1 protein in antisense ODN-treated kidneys, compared to reverse ODN treated and saline treated ischemic controls (P < 0.05). Antisense ODN also ameliorated the ischemia-induced infiltration of granulocytes and macrophages (P < 0.05), and resulted in less cortical renal damage as assessed by a quantitative pathological grading scale (P < 0.05), compared to reverse ODN or saline treatment. Thus, antisense ODN for ICAM-1 protected the kidney against ischemic renal failure. The clinical applicability of these findings extends beyond ischemic acute renal failure.
Haller
H
H
Franz Volhard Clinic, Max Delbrück Center for Molecular Medicine, Virchow Klinikum, Humboldt University of Berlin, Germany.
Dragun
D
D
Miethke
A
A
Park
J K
JK
Weis
A
A
Lippoldt
A
A
Gross
V
V
Luft
F C
FC
D058186:Acute Kidney Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000502:physiology*; D007668:Kidney / Q000098:blood supply* / Q000293:injuries* / Q000473:pathology; D008081:Liposomes; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D010714:Phosphatidylethanolamines; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
D008081:Liposomes; D016376:Oligonucleotides, Antisense; D010714:Phosphatidylethanolamines; D018799:Intercellular Adhesion Molecule-1; C020888:1,2-dielaidoylphosphatidylethanolamine