DESIGN: Prospective, controlled experimental study.
SETTING: University-based research laboratory.
SUBJECTS: C57BL/6 wild-type and DARC gene-deficient mice (DARC-/-).
INTERVENTIONS: MEASUREMENTS AND MAIN RESULTS: Plasma
creatinine and blood
urea nitrogen concentrations served as indicators of renal function or dysfunction.
Enzyme-linked
immunosorbent assays were used to measure tissue and plasma
chemokine concentrations. We also performed immunostaining to localize
chemokine expression and flow cytometry to evaluate neutrophil recruitment into the kidney. Following renal injury, wild-type mice developed moderate renal
ischemia-reperfusion(
lipopolysaccharide, 300% increase in plasma
creatinine concentrations) to severe
acute renal failure (renal
ischemia-reperfusion, 40% mortality) as well as extensive renal neutrophil recruitment. DARC-/- mice exhibited no renal dysfunction (renal
ischemia-reperfusion) or only very mild renal dysfunction (
lipopolysaccharide, 20% increase in serum
creatinine concentrations). DARC-/- mice showed no postischemic neutrophil infiltration. Although DARC-/- and wild-type mice exhibited similar global renal neutrophil-recruitment during
endotoxemia, DARC-/- mice showed significantly impaired neutrophil extravasation. Total renal concentrations of the
chemokine macrophage inflammatory protein 2, which has been shown to bind to DARC and to be crucial in postischemic
acute renal failure, were either identical (
lipopolysaccharide) or only moderately different (renal
ischemia-reperfusion) between wild-type and DARC-/- mice. Immunostaining revealed an absence of macrophage inflammatory protein-2 in renal endothelial cells of DARC-/- mice.
CONCLUSIONS: