The Duffy antigen receptor for chemokines (DARC) and acute renal failure (ARF) during lipopolysaccharide (LPS)-induced systemic inflammation

Background

Originally known as a target molecule for plasmodium vivax and as a blood group antigen, DARC has emerged as a promiscuous binding site for chemokines. Besides red blood cells, DARC is also expressed on endothelial cells, even in Duffy-negative individuals. However, the function of DARC during systemic inflammation remains unknown [1]. In a neutrophil (PMN)-dependent model of LPS-induced ARF [2], we sought to assess whether DARC plays a role in the development of organ failure during systemic inflammation.

Methods

ARF was induced by intraperitoneal injection of LPS in wild-type mice (WT) and DARC gene-deficient mice (DARC^-/-). At 4, 12, and 24 hours after injection, blood samples were drawn, and kidneys were removed. Plasma creatinine (Crea) as well as blood urea concentrations served as indicators of renal function, and renal myeloperoxidase activity (MPO) as an indicator of total renal PMN content. Untreated WT and DARC^-/- constituted corresponding control groups. Data analysis included ANOVA with subsequent multiple comparison analyses when appropriate.

Results

Over 24 hours, WT developed severe intrarenal ARF with a more than threefold increase in Crea. DARC^-/- on the other hand displayed a significant protection from ARF, exhibiting only a small, clinically irrelevant increase in Crea over 24 hours (Fig. 1). MPO was not different between WT and DARC^-/-; both groups showed significantly elevated renal MPO after LPS injection, peaking at 4 hours (Fig. 2) and declining thereafter. Even after LPS injection, RT-PCR failed to detect DARC mRNA expression in the kidney of WT, whereas it could demonstrate cerebral expression of DARC mRNA at 12 and 24 hours after LPS administration.

Figure 1

Critical Care March 2004 Vol 8 Suppl 1 24th International Symposium on Intensive Care and Emergency Medicine

Figure 2

Critical Care March 2004 Vol 8 Suppl 1 24th International Symposium on Intensive Care and Emergency Medicine

Conclusions

großee in the development of ARF. DARC seems to act via extrarenal (i.e. systemic) mechanisms and does not appear to alter the total renal PMN content.