Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbruck Center for Molecular Medicine, Berlin, Germany.
J Am Soc Nephrol. 2020 Apr;31(4):783-798. doi: 10.1681/ASN.2019060599. Epub 2020 Feb 21.
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 2A-adrenoceptors on sympathetic nerves, and 2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of 2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown.
We investigated effects of 2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and 2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days.
Urinary NE excretion and BP did not differ between normotensive 2A-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 2A-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 2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in 2A-adrenoceptor-deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in 2A-adrenoceptor-knockout mice after renal denervation.
Our findings reveal a protective role of prejunctional inhibitory 2A-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.
神经活动增加会导致高血压和肾脏疾病。最近的研究表明，肾脏去神经支配可降低高血压患者的血压。肾脏去甲肾上腺素（NE）的释放受交感神经上的预突触 2A-肾上腺素能受体调节，2A-肾上腺素能受体通过结合内源性 NE 作为自身受体发挥作用，从而抑制其自身释放。然而，2A-肾上腺素能受体在高血压性肾病发病机制中的作用尚不清楚。
我们研究了 2A-肾上腺素能受体调节的肾脏 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。在单侧肾切除的野生型和 2A-肾上腺素能受体敲除小鼠中，我们通过输注 AngII 28 天诱导高血压肾病。
在基线时，正常血压的 2A-肾上腺素能受体敲除小鼠与野生型小鼠的尿 NE 排泄和血压没有差异。然而，在 AngII 治疗期间，NE 排泄增加，敲除小鼠的 NE 水平明显高于野生型小鼠。相应地，2A-肾上腺素能受体敲除小鼠的收缩压升高，比野生型小鼠高约 40mmHg，并且肾脏损伤更严重。在分离的肾脏中，AngII 增强的肾神经刺激引起的 NE 释放和升压反应在 2A-肾上腺素能受体敲除小鼠的肾脏中更为明显。在缺乏 2A-肾上腺素能受体的肾脏中，激活特定的钠转运体伴随着高血压 BP 反应的夸大。这些作用依赖于肾脏神经，因为在 2A-肾上腺素能受体敲除小鼠进行肾脏去神经支配后，观察到 AngII 介导的高血压的严重程度降低和肾功能改善。
我们的发现揭示了在肾素-血管紧张素系统激活的病理生理条件下，预突触抑制性 2A-肾上腺素能受体具有保护作用，例如高血压性肾病，并支持交感神经切除作为治疗方法的概念。
