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. DESIGN: Prospective, controlled experimental study. SETTING: University-based research laboratory. SUBJECTS: C57BL/6 wild-type and DARC gene-deficient mice (DARC-/-). INTERVENTIONS: 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. 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: We suggest that DARC predominantly exerts its effects by controlling spatial chemokine distribution, which in turn regulates neutrophil recruitment and subsequent acute renal failure.

T cells modulate neutrophil-dependent acute renal failure during endotoxemia: critical role for CD28.

Sepsis still represents a leading cause of acute renal failure (ARF). Both lymphocytes and neutrophils (PMN) have been proposed as crucial mediators during sepsis. For further elucidation of the mechanisms of interactions between them, a murine model of LPS-induced ARF was used. In wild-type mice (WT), LPS administration led to a strong influx of PMN into the kidney (2.8-fold greater renal myeloperoxidase activity after 24 h) and to severe ARF (3.3-fold higher plasma creatinine concentrations after 24 h). By contrast, mice that were gene deficient for CD28 (CD28(-/-)), a co-stimulatory molecule for T cell activation, exhibited only minor renal dysfunction (50% protection compared with WT) and almost no PMN recruitment. When PMN(-) depleted, both WT and CD28(-/-) developed only mild ARF, similar to untreated CD28(-/-). Flow cytometry demonstrated that CD28 was vastly expressed on CD3(+) cells but not on PMN. Injecting wild-type CD3(+) cells into CD28(-/-) before LPS injection abolished the protection seen before. At baseline, both WT and CD28(-/-) displayed similar plasma concentrations of keratinocyte-derived chemokine (KC), a growth-related oncogene 1 gene product and PMN-specific chemokine. As opposed to WT, CD28(-/-) showed a greatly attenuated increase in plasma KC 4 h after LPS (2.5- versus 138.5-fold over controls, respectively). Moreover, CD28(-/-) showed less intense upregulation of renal growth-related oncogene 1 mRNA expression. Immunohistochemistry revealed considerable PMN but no T cell infiltrates in the kidney after LPS injection. In a PMN-dependent model of endotoxemic ARF, T cells, via the CD28 pathway, modulate kidney function and renal PMN recruitment. The effect on PMN is a remote one and presumably due to altered expression of PMN-specific chemokines.