Department of Surgery, Medical School, University of Minnesota, Minneapolis, Minnesota, United States.
Department of Physiology and Pathology, Dentistry School, São Paulo State University-UNESP, Araraquara, São Paulo, Brazil.
Am J Physiol Regul Integr Comp Physiol. 2023 Oct 1;325(4):R411-R422. doi: 10.1152/ajpregu.00072.2023. Epub 2023 Jul 31.
Renal denervation (RDN) is a potential therapy for drug-resistant hypertension. However, whether its effects are mediated by ablation of efferent or afferent renal nerves is not clear. Previous studies have implicated that renal inflammation and the sympathetic nervous system are driven by the activation of afferent and efferent renal nerves. RDN attenuated the renal inflammation and sympathetic activity in some animal models of hypertension. In the 2 kidney,1 clip (2K1C) model of renovascular hypertension, RDN also decreased sympathetic activity; however, mechanisms underlying renal and central inflammation are still unclear. We tested the hypothesis that the mechanisms by which total RDN (TRDN; efferent + afferent) and afferent-specific RDN (ARDN) reduce arterial pressure in 2K1C rats are the same. Male Sprague-Dawley rats were instrumented with telemeters to measure mean arterial pressure (MAP), and after 7 days, a clip was placed on the left renal artery. Rats underwent TRDN, ARDN, or sham surgery of the clipped kidney and MAP was measured for 6 wk. Weekly measurements of water intake (WI), urine output (UO), and urinary copeptin were conducted, and urine was analyzed for cytokines/chemokines. Neurogenic pressor activity (NPA) was assessed at the end of the protocol calculated by the depressor response after intraperitoneal injection of hexamethonium. Rats were euthanized and the hypothalamus and kidneys removed for measurement of cytokine content. MAP, NPA, WI, and urinary copeptin were significantly increased in 2K1C-sham rats, and these responses were abolished by both TRDN and ARDN. 2K1C-sham rats presented with renal and hypothalamic inflammation and these responses were largely mitigated by TRDN and ARDN. We conclude that RDN attenuates 2K1C hypertension primarily by ablation of afferent renal nerves which disrupts bidirectional renal neural-immune pathways. Hypertension resulting from reduced perfusion of the kidney is dependent on renal sensory nerves, which are linked to inflammation in the kidney and hypothalamus. Afferent renal nerves are required for chronic increases in both water intake and vasopressin release observed following renal artery stenosis. Findings from this study suggest an important role of renal sensory nerves that has previously been underestimated in the pathogenesis of 2K1C hypertension.
肾脏去神经（RDN）是治疗耐药性高血压的一种潜在疗法。然而，其效果是否通过传出或传入肾神经的消融来介导尚不清楚。先前的研究表明，肾脏炎症和交感神经系统是由传入和传出肾神经的激活所驱动的。在一些高血压动物模型中，RDN 减轻了肾脏炎症和交感活性。在肾血管性高血压的 2 肾 1 夹（2K1C）模型中，RDN 也降低了交感活性；然而，肾脏和中枢炎症的机制仍不清楚。我们检验了这样一个假设，即总 RDN（TRDN；传出+传入）和传入特异性 RDN（ARDN）降低 2K1C 大鼠动脉压的机制是相同的。雄性 Sprague-Dawley 大鼠被植入遥测仪以测量平均动脉压（MAP），并且在 7 天后，在左肾动脉上放置夹子。大鼠接受 TRDN、ARDN 或夹闭肾的假手术，MAP 测量 6 周。每周测量水摄入量（WI）、尿量（UO）和尿 copeptin，并分析尿液中的细胞因子/趋化因子。在方案结束时评估神经原性升压活性（NPA），通过腹腔注射六烃季铵后的降压反应来计算。大鼠被安乐死，取出下丘脑和肾脏进行细胞因子含量测量。2K1C-假手术大鼠的 MAP、NPA、WI 和尿 copeptin 显著增加，这两种反应均被 TRDN 和 ARDN 消除。2K1C-假手术大鼠表现出肾脏和下丘脑炎症，这些反应主要被 TRDN 和 ARDN 减轻。我们得出结论，RDN 通过消融传入肾神经主要减轻 2K1C 高血压，从而破坏双向肾神经免疫途径。肾灌注减少引起的高血压依赖于肾脏感觉神经，而肾脏感觉神经与肾脏和下丘脑的炎症有关。传入肾神经是肾动脉狭窄后观察到的水摄入和血管加压素释放的慢性增加所必需的。这项研究的结果表明，在 2K1C 高血压的发病机制中，肾脏感觉神经的作用以前被低估了，这是一个重要的作用。
