Endothelin-A receptor blockade improves renal microvascular architecture and function in experimental hypercholesterolemia

Hypercholesterolemia (HC) may trigger early renal injury, partly by impairing the function or the structure of renal microvessels (MV). The endothelin (ET) system is upregulated in HC and can have an impact on the renal microcirculation by regulating MV tone, growth factors, and remodeling. It was hypothesized that ET-A blockade would protect the HC kidney by improving the function and attenuating the damage of intrarenal MV. Single-kidney function and hemodynamic responses to endothelium-dependent challenge were assessed in pigs after 12 wk of experimental HC, HC and chronic supplementation with the ET receptor A blocker ABT-627 (HC+ET-A, 0.75 mg/kg per d), and normal controls. Renal MV architecture then was studied ex vivo using three-dimensional microcomputed tomography imaging, and growth factors and remodeling pathways were explored in renal tissue. The HC kidney showed increased MV density compared with normal (77.68 ± 5.1 versus 62.9 ± 4.8 vessels/cm²; P = 0.04) but blunted endothelial function. Chronic ET-A blockade in HC upregulated renal vascular growth factors, further increased renal MV density (139.9 ± 8.4 vessels/cm²; P = 0.001 versus normal and HC), and decreased renal tissue and MV remodeling. Furthermore, ET-A blockade in HC decreased MV tortuosity and improved MV endothelial function, suggesting accelerated stabilization and maturation of neo-vessels. Modulation of renal MV architecture and function in HC is mediated partly by the endogenous ET system. Notably, ET-A blockade enhanced the proliferation and facilitated the maturation of renal MV in the HC kidney and improved renal MV remodeling and function. This study suggests novel renoprotective effects of ET-A blockers and supports further exploration of strategies that target the ET pathway in HC and atherosclerosis.