BACKGROUND Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown. METHODS We investigated effects of α2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days. RESULTS Urinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor-knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor-knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor-deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor-knockout mice after renal denervation. CONCLUSIONS Our findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.

中文翻译：

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α2A-肾上腺素能受体调节肾交感神经传递并预防高血压肾脏疾病。

背景技术神经活动增加导致高血压和肾脏疾病。最近的研究表明，肾脏去神经支配能降低高血压患者的血压。交感神经上的结前α2A肾上腺素受体调节肾NE的释放，而α2A肾上腺素受体通过结合内源性NE抑制自身释放而充当自体受体。然而，α2A-肾上腺素受体在高血压肾脏疾病的发病机理中的作用尚不清楚。方法我们研究了α2A-肾上腺素受体调节的肾脏NE释放对血管紧张素II依赖性高血压和肾脏疾病发展的影响。在未切除直肠的野生型和α2A肾上腺素受体敲除小鼠中，我们通过输注AngII 28天诱发了高血压肾脏疾病。结果基线血压正常的α2A-肾上腺素受体敲除小鼠和野生型小鼠之间的尿NE排泄和血压没有差异。但是，在AngII治疗期间，NE的排泄增加，基因敲除小鼠的NE水平明显高于野生型小鼠。因此，α2A-肾上腺素受体敲除小鼠表现出收缩压增加，其比野生型小鼠高约40mm Hg，并且肾脏损害更大。在孤立的肾脏中，AngII增强的肾神经刺激在更大程度上诱导了来自α2A-肾上腺素受体敲除小鼠的肾脏中NE的释放和升压反应。在α2A-肾上腺素受体缺乏的肾脏中，特定的钠转运蛋白的活化伴随着过度的高血压BP反应。这些影响取决于肾神经，如在肾去神经支配后在α2A-肾上腺素受体敲除小鼠中观察到的AngII介导的高血压严重程度降低和肾功能改善所证明。结论我们的发现揭示了结节抑制性α2A肾上腺素能受体在激活的肾素-血管紧张素系统（例如高血压肾脏疾病）的病理生理状况中的保护作用，并支持了交感神经疗法作为治疗的概念。