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Protection from ischemia-reperfusion induced severe acute renal failure by blocking E-selectin
1Department of Biomedical Engineering, University of Virginia, Charlottesville 22908-0395, USA.
Objective:
Despite progress in renal replacement therapy and critical care medicine, acute renal failure (ARF) still carries a very high mortality rate. Neutrophil infiltration has been recognized as a hallmark in postischemic renal injury. Neutrophil recruitment requires adhesion molecules including E-selectin, which mediates leukocyte rolling and adhesion. This study aims to identify the role of E-selectin in ischemia-reperfusion-induced severe ARF.
Design:
Prospective, controlled, experimental study.
Setting:
University animal research laboratory.
Subjects:
C57BL/6 wild-type mice or C57BL/6 mice gene-deficient for E-selectin.
Interventions:
Mice underwent 32-min bilateral renal ischemia or identical sham operations. After 4, 12, 24, or 48 hrs, kidneys were harvested and blood samples were taken. A separate group of wild-type mice received either antineutrophil serum or control serum 18 hrs before ischemia. Another group of wild-type mice was injected with function-blocking monoclonal E-selectin antibody or with control antibody 10 mins after reperfusion. Blood samples were taken 24 hrs later.
Measurements And Main Results:
Blood creatinine and urea nitrogen concentrations, as well as renal myeloperoxidase activity indicating neutrophil infiltration, were measured. Reducing neutrophil counts by antineutrophil serum showed that in this model, organ failure strongly depends on neutrophil counts at time of ischemia. E-selectin deficient mice showed lower creatinine and blood urea nitrogen concentrations than wild-type mice at 24 and 48 hrs (a reduction of 60% to 80%). Kidneys of E-selectin deficient mice also revealed a lower myeloperoxidase activity maximum (75% reduction) at 24 hrs. Western blot analysis showed maximum E-selectin expression 24 hrs after ischemia-reperfusion. Immunostaining localized E-selectin to the endothelium of the peritubular capillary plexus. Compared with control antibody, postischemic injection of anti-E-selectin antibody gave lower creatinine concentrations at 24 hrs, similar to that seen in E-selectin deficient mice.
Conclusions:
In this model, blocking E-selectin even after onset of reperfusion protects from severe ARF, presumably by reducing postischemic neutrophil infiltration into the kidney. This suggests a new potential therapeutic perspective.