Endothelin‐A Receptor Blockade Improves Angiogenic Signaling in the Stenotic Kidney

Abstract

BackgroundChronic renal artery stenosis (RAS) induces endothelin (ET)‐1 up‐regulation and via the ET‐A receptor can promote renal injury. Chronic RAS promotes renal microvascular (MV) damage and loss but the role of the ET/ET‐A is unknown. Thus, we hypothesized that ET‐A blockade in RAS will preserve the MV architecture by improving the angiogenic signaling in the stenotic kidney.MethodsRAS was induced in 12 pigs and observed for 6 weeks. In 6 of them, ET‐A blocker was chronically administered (RAS+ET‐A, 0.75 mg/kg/day). Additional animals were used as normal controls (n=6). Single‐kidney MV architecture and function was quantified using CT and renal angiogenic and apoptotic signaling determined by western blot.ResultsET‐A blockade in RAS improved the renal expression of VEGF and augmented downstream mediators such as angiopoietin‐1 and 2, its receptor Tie‐2, and eNOS. Interestingly, it also decreased Bax/Bcl‐2 ratio, suggesting attenuated apoptotic signaling in the stenotic kidney. Consequently, MV density and function in the RAS+ET‐A kidney was improved.ConclusionChronic ET‐A blockade improved angiogenic and decreased apoptotic signaling in the stenotic kidney. These ultimately preserved the renal MV architecture and function in the stenotic kidney, supporting a novel renoprotective role of ET‐A blockade in chronic RAS.Support: AHA‐SDG‐0830100N