Macrophages, which exhibit great pliability, are important components of renal ischemic reperfusion injury (IRI) and are closely correlated with loss of renal function. Chemokine Receptor (CCR) 5 signaling is involved in mechanisms of inflammation, and expression of chemokine (C-X-C motif) receptor by macrophages has been reported. We aim to determine the effect of macrophage phenotype on the expression of CCR5, the influence of the macrophage phenotype in activation of CCR5 signaling and the relevance of this pathway in IRI.

Bilateral renal artery pedicles clamping for 30 min followed by reperfusion was performed to B6 wild type and CCR5 KO mice in order to investigate the functional role of macrophage/CCR5 in IRI. CCR5 KO mice showed less aggravated IRI in terms of the apoptosis of tubular epithelial cells and creatinine compare to B6 wild type. The absence of T cells in B6 wild type mice activated greater number of M2 macrophage cells and this led to attenuation of the severe renal injury, whereas maintaining T cells accentuated injury. However, we could not find significant difference of the renal injury in the CCR5 KO mice, irrespective of T cell depletion. Intra-renal mRNA expressions of IL-10, arginase1 and Mac2 were up-regulated in CCR5 KO mice rendered IRI, and the levels of those mRNA were increased following the deletion of T cells. Moreover, CXCR3 positivity in CD11b+ cells and iNOS were decreased in CCR5 KO mice compared to that in B6 wild type mice. CCR5 KO mice bone marrow-derived macrophages were polarized towards CD206+M2 phenotype. The expressions of IL-10 effectively increased during the differentiation processes of macrophage cells. TAK 779, combined CXCR3 and CCR5 blockade, is effective in preventing apoptosis of renal tubular cells after transient hypoxia. Renal tissue of patients with delayed graft function frequently contained CCR5 cells, and the number of these cells tended to positively correlate with acute tubular necrosis severity.

These findings show that M1 macrophages, but not M2, activate CCR5 on macrophage signaling pathways and that T cell is less involved in polarization of macrophages. Blocking CCR5 may provide a potential strategy for treating acute kidney injury.

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