The Duffy antigen receptor for chemokines in acute renal failure: A facilitator of renal chemokine presentation.
OBJECTIVE
Acute renal failure remains a major challenge in critical care medicine. Both neutrophils and chemokines have been proposed as key components in the development of acute renal failure. Although the Duffy antigen receptor for chemokines (DARC) is present in several tissues and a highly specific ligand for various chemokines, its exact role in vivo remains unclear.


METHODS
Prospective, controlled experimental study.


METHODS
University-based research laboratory.


METHODS
C57BL/6 wild-type and DARC gene-deficient mice (DARC-/-).


METHODS
To unravel the functional relevance of DARC in vivo, we compared wild-type and DARC-/- using neutrophil-dependent models of acute renal failure, induced by either local (renal ischemia-reperfusion) or systemic (endotoxemia, lipopolysaccharide) injury.


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
We suggest that DARC predominantly exerts its effects by controlling spatial chemokine distribution, which in turn regulates neutrophil recruitment and subsequent acute renal failure.
Zarbock
Alexander
A
Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Münster, Germany.
Schmolke
Mirco
M
Bockhorn
Susanne Grosse
SG
Scharte
Marion
M
Buschmann
Kirsten
K
Ley
Klaus
K
Singbartl
Kai
K
D000818:Animals; D051379:Mice; D058186:Acute Kidney Injury / Q000503:physiopathology; D001806:Blood Urea Nitrogen; D018925:Chemokines / Q000032:analysis; D003404:Creatinine / Q000097:blood; D004375:Duffy Blood-Group System / Q000235:genetics / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000502:physiology; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology
D018925:Chemokines; D003404:Creatinine; D004375:Duffy Blood-Group System; D011956:Receptors, Cell Surface; C483025:Ackr1 protein mouse