Abstract P236: Role Of Axl In Target Organ Inflammation And Damage Due To Hypertensive Aortic Remodeling

Background: Aortic remodeling enhances arterial pulsatility in the microcirculation and we have shown that excessive endothelial stretch increases release of Growth Arrest Specific 6 (GAS6), which activates Axl on monocytes causing immune activation and inflammation. Hypothesis: GAS6/Axl blockade reduces renal and vascular inflammation and lessens renal dysfunction caused by aortic remodeling. Methods and Results: Three month old male C57Bl/6 mice received osmotic minipumps containing vehicle or ang II for 2 weeks and the pumps removed. Aortas demonstrated increased collagen and an 80% loss of Windkessel function that persisted for 6 months following ang II. Renal function studies showed 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 aortic and renal infiltration of T cells, gamma/delta T cells and macrophages as measured by flow cytometry (Figure). R428 also improved renal excretory capacity, decreased urinary NGAL, reduced albuminuria, and attenuated renal tubular damage. Interestingly, macrophage/T cell complexes were present in aortas of mice previously exposed to hypertension, and were reduced by R428. Conclusion: Brief episodes of hypertension induce chronic aortic remodeling which increases Axl signaling and transformation of monocytes to inflammatory antigen presenting cells that activate T cells. Axl blockade might serve as a therapeutic option to improve end-organ damage after an episode of hypertension.