Comparison between VDR analogs and current immunosuppressive drugs in relation to CXCL10 secretion by human renal tubular cells

Abstract

During kidney allograft rejection, CXC chemokine ligand 10 (CXCL10)-CXC chemokine receptor 3 (CXCR3) trafficking between peripheral blood and tissues initiates alloresponse and perpetuates a self-inflammatory loop; thus, CXCL10-CXCR3 axis could represent a pharmacologic target. In this perspective, immunosuppressors targeting graft-resident cells, beside immune cells, could be very advantageous. Vitamin D receptor (VDR) agonists exhibit considerable immunomodulatory properties. This study aimed to investigate whether elocalcitol and BXL-01-0029 could decrease the expression of CXCL10 in activated renal tubular cells in vitro and thus be useful in kidney allograft rejection treatment. Experiments were performed in human tubular renal cells stimulated with interferon-gamma + tumor necrosis factor-alpha with and without VDR agonists, tacrolimus, sirolimus, hydrocortisone, methylprednisolone, cyclosporin A and mycophenolate mofetil. CXCL10 protein secretion and gene expression were measured by ELISA and by quantitative PCR. Specific inhibitors were used to investigate intracellular pathways involved in tubular cells activation. For IC(50) determination and comparison, dose-response curves with VDR agonists, tacrolimus and mycophenolic acid were performed. Elocalcitol and BXL-01-0029 inhibited CXCL10 secretion by renal cells, without affecting cell viability, while almost all the immunosuppressors were found to be ineffective, except for tacrolimus and mycophenolate mofetil. BXL-01-0029 was the most potent drug and, notably, it was found to be capable of allowing reduction in tacrolimus-inhibitory doses. Our data suggest that BXL-01-0029 could potentially be a dose-reducing agent for conventional immunosuppressors in kidney rejection management.