Targeting AXL cellular networks in kidney fibrosis

Abstract

Introduction: The incidence of chronic kidney disease (CKD) is increasing, in parallel with risk factors including obesity and diabetes mellitus. AXL plays a central role in CKD, providing a rationale to evaluate clinical AXL targeting agents.

Methods: To determine the efficacy and underlying molecular mechanisms of AXL inhibition in CKD, we employed a murine unilateral ureteral obstruction (UUO) model preventively treated with a selective AXL kinase inhibitor (bemcentinib) during disease progression. We isolated kidneys at an early (3 days) or late (15 days) timepoint and profiled the cell populations using mass cytometry.

Results: Preventive treatment with bemcentinib significantly attenuated fibrosis in the UUO model. The anti-fibrotic effect correlated with a decrease in mesangial cells and inhibition of innate immune cell infiltration, while the proportion of epithelial cells increased. We mapped AXL expression to a unique network of cells in the kidney: mesangial cells, pericytes, macrophages and dendritic cells.

Discussion: We propose that AXL targeting affects an important cellular interaction network underlying fibrotic progression. These results support the clinical application of AXL targeting agents to treat CKD.

Keywords: Axl; UUO (unilateral ureteral obstruction); bemcentinib; fibrosis; inflammation; mass cytometry (CyTOF).