Role of Axl in target organ inflammation and damage due to hypertensive aortic remodeling

Excessive endothelial cell stretch causes release of Growth Arrest Specific 6 (GAS6), which activates the tyrosine kinase receptor Axl on monocytes and promotes immune activation and inflammation. We hypothesized that GAS6/Axl blockade would reduce renal and vascular inflammation and lessen renal dysfunction in the setting of chronic aortic remodeling. We characterized a model of aortic remodeling in mice following a 2-week infusion of angiotensin II (ang II). These mice had chronically increased pulse wave velocity and their aortas demonstrated increased mural Collagen. Mechanical testing revealed a marked loss of Windkessel function that persisted for 6 months following ang II. Renal function studies showed a reduced ability to excrete a volume load, a progressive increase in albuminuria and tubular damage as estimated by Periodic Acid Schiff staining. Treatment with the Axl Inhibitor R428 beginning 2 months after ang II had minimal effect on aortic remodeling 2 months later, but reduced the infiltration of T cells, g/d T cells and macrophages into the aorta and kidney, and improved renal excretory capacity, reduced albuminuria, and reduced evidence of renal tubular damage. In humans, circulating Axl⁺/Siglec6⁺ dendritic cells and phosphoAxl⁺ cells correlated with pulse wave velocity and aortic compliance measured by transesophageal echo, confirming chronic activation of the GAS6/Axl pathway. We conclude that brief episodes of hypertension induce chronic aortic remodeling which associates with persistent low-grade inflammation of the aorta and kidneys and evidence of renal dysfunction. These events are mediated at least in part by GAS6/Axl signaling and are improved with Axl blockade.