Protection from ischemia-reperfusion induced severe acute renal failure byblocking E-selectin

Objective: Despite progress in renal replacement therapy and critical care medicine, acute renal failure (ARF) still carries a very high mortality rat e. Neutrophil infiltration has been recognized as a hallmark in postischemi c renal injury, Neutrophil recruitment requires adhesion molecules includin g E-selectin, which mediates leukocyte rolling and adhesion. This study aim s 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-selec tin. Interventions: Mice underwent 32-min bilateral renal ischemia or identical sham operations. After 4, 12, 24, or 48 hrs, kidneys were harvested and blo od samples were taken, A separate group of wild-type mice received either a ntineutrophil 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 concentra tions, as well as renal myeloperoxidase activity indicating neutrophil infi ltration, were measured. Reducing neutrophil counts by antineutrophil serum showed that in this model, organ failure strongly depends on neutrophil co unts at time of ischemia, E-selectin deficient mice showed lower creatinine and blood urea nitrogen concentrations than wild-type mice at 24 and 48 hr s (a reduction of 60% to 80%). Kidneys of E-selectin deficient mice also re vealed a lower myeloperoxidase activity maximum (75% reduction) at 24 hrs, Western blot analysis showed maximum E-selectin expression 24 hrs after isc hemia-reperfusion. Immunostaining localized E-selectin to the endothelium o f the peritubular capillary plexus, Compared with control antibody, postisc hemic injection of anti-E-selectin antibody gave lower creatinine concentra tions at 24 hrs, similar to that seen in E-selectin deficient mice. Conclusions: In this model, blocking E-selectin even after onset of reperfu sion protects from severe ARF, presumably by reducing postischemic neutroph il infiltration into the kidney. This suggests a new potential therapeutic perspective.