From the Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research (S.C.C., O.B., A.C., S.O., J.C.F.-A., T.B., P.P., E.L.S.), and Department of Medicine (E.L.S.), Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Québec, Canada; and Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Ludwigstrasse, Bad Nauheim, Germany (S.O.).
Hypertension. 2018 Jan;71(1):208-216. doi: 10.1161/HYPERTENSIONAHA.117.09925. Epub 2017 Nov 13.
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 (ET) 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 ET receptor blocker atrasentan for 2 weeks. Three-month induction of endothelial human ET-1 overexpression increased blood pressure (<0.01), reduced renal artery flow (<0.001), and caused mesenteric small artery stiffening (<0.05) and endothelial dysfunction (<0.01). These changes were accompanied by enhanced mesenteric small artery and expression, and perivascular adipose tissue oxidative stress (<0.05) and monocyte/macrophage infiltration (<0.05). Early renal injury was demonstrated by increased kidney injury molecule-1 expression in renal cortex tubules (<0.05), with, however, undetectable lesions using histochemistry staining and unchanged urinary albumin. There was associated increased myeloid (CD11b) and myeloid-derived suppressive cell (CD11bGr-1) renal infiltration (<0.01) and greater frequency of myeloid and renal cells expressing the proinflammatory marker CD36 (<0.05). Atrasentan reversed or reduced all of the above changes (<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 ET receptors.
内皮细胞衍生的内皮素（ET）-1 被认为与高血压和终末器官损伤的发生有关，但确切作用尚不清楚。我们已经表明，在不存在血管和肾脏损伤的情况下，3 周诱导后，他莫昔芬诱导的内皮细胞特异性人 ET-1 过表达（ieET-1）小鼠以 ET 型 A（ET）受体依赖性方式表现出血压升高。尚不清楚长期 ET-1 过表达是否会导致持续的血压升高以及血管和肾脏损伤。成年雄性 ieET-1 和对照他莫昔芬诱导的内皮细胞特异性 Cre 重组酶（ieCre）小鼠用他莫昔芬诱导，2.5 个月后，用或不用 ET 受体阻滞剂 atrasentan 治疗 2 周。内皮细胞特异性人 ET-1 过表达 3 个月诱导增加血压（<0.01），降低肾动脉血流量（<0.001），并导致肠系膜小动脉僵硬（<0.05）和内皮功能障碍（<0.01）。这些变化伴随着肠系膜小动脉和的表达增强，以及血管周围脂肪组织氧化应激（<0.05）和单核细胞/巨噬细胞浸润（<0.05）。早期肾损伤表现为肾皮质肾小管中肾损伤分子-1 表达增加（<0.05），但组织化学染色未检测到病变，尿白蛋白不变。同时伴有骨髓（CD11b）和骨髓源性抑制细胞（CD11bGr-1）肾浸润增加（<0.01）和表达促炎标志物 CD36 的骨髓和肾细胞频率增加（<0.05）。Atrasentan 逆转或减少了所有上述变化（<0.05），除了内皮功能障碍和胶原表达以及肾动脉血流量减少。这些结果表明，长期暴露于人内皮细胞 ET-1 过表达会通过 ET 受体导致持续的血压升高和血管及肾脏损伤。
