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Endothelium-derived endothelin (ET)-1 has been implicated in the development of hypertension and end-organ damage, but its exact role remains unclear. We have shown that tamoxifen-inducible endothelium-restricted human ET-1 overexpressing (ieET-1) mice exhibited blood pressure rise after a 3-week induction in an ET type A (ETA ) receptor-dependent manner, in absence of vascular and renal injury. It is unknown whether long-term ET-1 overexpression results in sustained blood pressure elevation and vascular and renal injury. Adult male ieET-1 and control tamoxifen-inducible endothelium-restricted Cre recombinase (ieCre) mice were induced with tamoxifen and 2.5 months later, were treated with or without the ETA receptor blocker atrasentan for 2 weeks. Three-month induction of endothelial human ET-1 overexpression increased blood pressure (P &lt;0.01), reduced renal artery flow (P &lt;0.001), and caused mesenteric small artery stiffening (P &lt;0.05) and endothelial dysfunction (P &lt;0.01). These changes were accompanied by enhanced mesenteric small arteryCol1A1 andCol3A1 expression, and perivascular adipose tissue oxidative stress (P &lt;0.05) and monocyte/macrophage infiltration (P &lt;0.05). Early renal injury was demonstrated by increased kidney injury molecule-1 expression in renal cortex tubules (P &lt;0.05), with, however, undetectable lesions using histochemistry staining and unchanged urinary albumin. There was associated increased myeloid (CD11b+ ) and myeloid-derived suppressive cell (CD11b+ Gr-1+ ) renal infiltration (P &lt;0.01) and greater frequency of myeloid and renal cells expressing the proinflammatory marker CD36 (P &lt;0.05). Atrasentan reversed or reduced all of the above changes (P &lt;0.05) except the endothelial dysfunction and collagen expression and reduced renal artery flow. These results demonstrate that long-term exposure to endothelial human ET-1 overexpression causes sustained blood pressure elevation and vascular and renal injury via ETA receptors.

Three-Month Endothelial Human Endothelin-1 Overexpression Causes Blood Pressure Elevation and Vascular and Kidney Injury