Relative Roles of CCL5 on Podocytes and Macrophages in Glomerular Injury

Background: We had previously reported that Notch2 activation reduces podocyte damage, and now we have identified and analyzed C-C motif chemokine ligand 5 (CCL5) as the downstream molecule. CCL5 is a secreted protein that acts on macrophages (Mφ), T cells, and epithelial cells, but its role in glomerular injury is controversial. An earlier study has shown that a functional CCL5 antagonist attenuates glomerulonephritis, while another study reported that it exacerbates glomerular damage in glomerular disease models. Using in vitro and in vivo studies, we delved into the role of CCL5 in podocytes and bone marrow-derived cells. Methods: We performed immunostaining of human kidney samples to investigate the expression of CCL5 in glomerular disease. Cultured CCL5 knockout (KO) podocytes and CCL5 KO mice were created. Cultured WT podocytes and CCL5 KO podocytes were treated with adriamycin (ADR), and then the apoptosis rate was evaluated. WT and CCL5 KO mice were injected with ADR to induce nephropathy, and then we investigated the kidney pathology. We performed bone marrow transplantation in WT and CCL5 KO mice to study the CCL5 function in podocytes or bone marrow-derived cells. Results: We found that CCL5 expression in glomeruli was upregulated in patients with glomerular disease and in ADR-induced nephropathy mice. ADR-induced injury in cultured WT podocytes was ameliorated by exogenous CCL5 administration and exacerbated by CCL5 deficiency. These in vitro studies suggested that CCL5 has a protective role in injured podocytes. Next, to check the role of CCL5 in vivo, ADR nephropathy mice were used. Unexpectedly, ADR-induced nephropathy was ameliorated in CCL5 KO mice. To elucidate the discrepancy, we transplanted the bone marrow of CCL5 KO mice to ADR-induced nephropathy WT mice. The transplantation of CCL5 KO bone marrow ameliorated the ADR-induced nephropathy in the WT mice. Conclusion: CCL5 exacerbates ADR nephropathy via bone marrow-derived cells but plays a protective role in podocytes. The results suggest that CCL5 has ambivalent cellular effects in glomerular diseases.