Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota.
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska.
Am J Physiol Heart Circ Physiol. 2019 Nov 1;317(5):H958-H968. doi: 10.1152/ajpheart.00299.2019. Epub 2019 Sep 6.
Previously we have shown that increased expression of renal epithelial sodium channels (ENaC) may contribute to the renal sodium and water retention observed during chronic heart failure (CHF). The goal of this study was to examine whether renal denervation (RDN) changed the expressions of renal sodium transporters ENaC, sodium-hydrogen exchanger-3 proteins (NHE3), and water channel aquaporin 2 (AQP2) in rats with CHF. CHF was produced by left coronary artery ligation in rats. Four weeks after ligation surgery, surgical bilateral RDN was performed. The expression of ENaC, NHE3, and AQP2 in both renal cortex and medulla were measured. As a functional test for ENaC activation, diuretic and natriuretic responses to ENaC inhibitor benzamil were monitored in four groups of rats (Sham, Sham+RDN, CHF, CHF+RDN). Western blot analysis indicated that RDN (1 wk later) significantly reduced protein levels of α-ENaC, β-ENaC, γ-ENaC, and AQP2 in the renal cortex of CHF rats. RDN had no significant effects on the protein expression of kidney NHE3 in both Sham and CHF rats. Immunofluorescence studies of kidney sections confirmed the reduced signaling of ENaC and AQP2 in the CHF+RDN rats compared with the CHF rats. There were increases in diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. RDN reduced the diuretic and natriuretic responses to benzamil in CHF rats. These findings suggest a critical role for renal nerves in the enhanced expression of ENaC and AQP2 and subsequent pathophysiology of renal sodium and water retention associated with CHF. This is the first study to show in a comprehensive way that renal denervation initiated after a period of chronic heart failure reduces the expression of epithelial sodium channels and aquaporin 2 leading to reduced epithelial sodium channel function and sodium retention.
先前的研究表明，肾脏上皮钠通道（ENaC）表达增加可能导致慢性心力衰竭（CHF）期间观察到的肾脏钠水潴留。本研究的目的是探讨肾去神经（RDN）是否改变心力衰竭大鼠肾脏钠转运体 ENaC、钠-氢交换蛋白 3（NHE3）和水通道 aquaporin 2（AQP2）的表达。通过左冠状动脉结扎在大鼠中产生 CHF。结扎手术后 4 周，进行双侧 RDN 手术。测量肾脏皮质和髓质中 ENaC、NHE3 和 AQP2 的表达。作为 ENaC 激活的功能测试，监测了四组大鼠（Sham、Sham+RDN、CHF、CHF+RDN）对 ENaC 抑制剂苯并咪的利尿和排钠反应。Western blot 分析表明，RDN（1 周后）显著降低了心力衰竭大鼠肾脏皮质中α-ENaC、β-ENaC、γ-ENaC 和 AQP2 的蛋白水平。RDN 对 Sham 和 CHF 大鼠肾脏 NHE3 的蛋白表达均无显著影响。肾脏切片免疫荧光研究证实，与 CHF 大鼠相比，CHF+RDN 大鼠 ENaC 和 AQP2 的信号传递减少。心力衰竭大鼠对 ENaC 抑制剂苯并咪的利尿和排钠反应增加。RDN 降低了心力衰竭大鼠对苯并咪的利尿和排钠反应。这些发现表明，肾脏神经在增强 ENaC 和 AQP2 的表达以及随后与 CHF 相关的肾脏钠水潴留的病理生理中起关键作用。这是第一项全面研究表明，慢性心力衰竭后一段时间开始的肾去神经可降低上皮钠通道和水通道 aquaporin 2 的表达，从而导致上皮钠通道功能降低和钠潴留。
