The therapeutic potential of an allosteric non‐competitive CXCR1/2 antagonist for diabetic nephropathy

Abstract

AbstractAimsDiabetic nephropathy is a major consequence of inflammation developing in type 1 diabetes, with interleukin‐8 (IL‐8)‐CXCR1/2 axis playing a key role in kidney disease progression. In this study, we investigated the therapeutic potential of a CXCR1/2 non‐competitive allosteric antagonist (Ladarixin) in preventing high glucose‐mediated injury in human podocytes and epithelial cells differentiated from renal stem/progenitor cells (RSC) cultured as nephrospheres.Materials and MethodsWe used human RSCs cultured as nephrospheres through a sphere‐forming functional assay to investigate hyperglycemia‐mediated effects on IL‐8 signalling in human podocytes and tubular epithelial cells.ResultsHigh glucose impairs RSC self‐renewal, induces an increase in IL‐8 transcript expression and protein secretion and induces DNA damage in RSC‐differentiated podocytes, while exerting no effect on RSC‐differentiated epithelial cells. Accordingly, the supernatant from epithelial cells or podocytes cultured in high glucose was able to differentially activate leucocyte‐mediated secretion of pro‐inflammatory cytokines, suggesting that the crosstalk between immune and non‐immune cells may be involved in disease progression in vivo.ConclusionsTreatment with Ladarixin during RSC differentiation prevented high glucose‐mediated effects on podocytes and modulated either podocyte or epithelial cell‐dependent leucocyte secretion of pro‐inflammatory cytokines, suggesting CXCR1/2 antagonists as possible pharmacological approaches for the treatment of diabetic nephropathy.