Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure.
Acute renal failure (ARF) in response to ischemia-reperfusion is thought to be associated with neutrophil infiltration. Neutrophil recruitment depends on adhesion molecules, including P-selectin. Our study sought to characterize the role of P-selectin in ischemia-reperfusion (I/R) -induced acute renal failure (ARF). In wild-type (wt) and P-selectin-deficient (P-/-) mice (both C57BL/6), ARF was induced by 32 min bilateral renal ischemia, followed by reperfusion (I/R). Wt showed a 12- and 20-fold increase in creatinine at 24 and 48 h after I/R, respectively. Similar changes were seen in blood urea nitrogen (BUN). By contrast, in P-/- creatinine and BUN increased only moderately (fourfold over sham). In wt, renal myeloperoxidase activity, indicating neutrophil infiltration, peaked after 24 h (19-fold over sham). This was significantly attenuated in P-/- (fivefold over sham). Western blot analysis revealed maximum P-selectin expression 12 h after I/R in wt. Immunostaining detected P-selectin in glomerular endothelium and in platelets adherent in glomerular and peritubular vessels. Postischemic injection of P-selectin antibody at 10 min after reperfusion, but not isotype control antibody, protected wt from ARF similar to the protection seen in P-/-. We conclude that blocking P-selectin even after onset of reperfusion protects mice from I/R-induced ARF, suggesting potential therapeutic strategies aimed at blocking P-selectin.
Singbartl
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Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA. l
Green
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Ley
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D058186:Acute Kidney Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009504:Neutrophils / Q000473:pathology; D019007:P-Selectin / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D015427:Reperfusion Injury / Q000150:complications*
D000911:Antibodies, Monoclonal; D019007:P-Selectin