Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Department of Medicine, University of Michigan, Ann Arbor, Michigan.
Am J Physiol Renal Physiol. 2022 Dec 1;323(6):F633-F641. doi: 10.1152/ajprenal.00107.2022. Epub 2022 Oct 6.
The activity of the epithelial Na channel (ENaC) in principal cells of the distal nephron fine-tunes renal Na excretion. The renin-angiotensin-aldosterone system modulates ENaC activity to control blood pressure, in part, by influencing Na excretion. NADPH oxidase activator 1-dependent NADPH oxidase 1 (NOXA1/NOX1) signaling may play a key role in angiotensin II (ANG II)-dependent activation of ENaC. The present study aimed to explore the role of NOXA1/NOX1 signaling in ANG II-dependent activation of ENaC in renal principal cells. Patch-clamp electrophysiology and principal cell-specific Noxa1 knockout (PC- KO) mice were used to determine the role of NOXA1/NOX1 signaling in ANG II-dependent activation of ENaC. The activity of ENaC in the luminal plasma membrane of principal cells was quantified in freshly isolated split-opened tubules using voltage-clamp electrophysiology. ANG II significantly increased ENaC activity. This effect was robust and observed in response to both acute (40 min) and more chronic (48-72 h) ANG II treatment of isolated tubules and mice, respectively. Inhibition of ANG II type 1 receptors with losartan abolished ANG II-dependent stimulation of ENaC. Similarly, treatment with ML171, a specific inhibitor of NOX1, abolished stimulation of ENaC by ANG II. Treatment with ANG II failed to increase ENaC activity in principal cells in tubules isolated from the PC- KO mouse. Tubules from wild-type littermate controls, though, retained their ability to respond to ANG II with an increase in ENaC activity. These results indicate that NOXA1/NOX1 signaling mediates ANG II stimulation of ENaC in renal principal cells. As such, NOXA1/NOX1 signaling in the distal nephron plays a central role in Na homeostasis and control of blood pressure, particularly as it relates to regulation by the renin-ANG II axis. Activity of the epithelial Na channel (ENaC) in the distal nephron fine-tunes renal Na excretion. Angiotensin II (ANG II) has been reported to enhance ENaC activity. Emerging evidence suggests that NADPH oxidase (NOX) signaling plays an important role in the stimulation of ENaC by ANG II in principal cells. The present findings indicate that NOX activator 1/NOX1 signaling mediates ANG II stimulation of ENaC in renal principal cells.
远端肾单位主细胞中上皮钠通道 (ENaC) 的活性可精细调节肾脏钠排泄。肾素-血管紧张素-醛固酮系统通过影响钠排泄来调节 ENaC 活性，从而调节血压。NADPH 氧化酶激活物 1 依赖性 NADPH 氧化酶 1 (NOXA1/NOX1) 信号可能在血管紧张素 II (ANG II) 依赖性 ENaC 激活中发挥关键作用。本研究旨在探讨 NOXA1/NOX1 信号在 ANG II 依赖性主细胞 ENaC 激活中的作用。使用膜片钳电生理学和主细胞特异性 Noxa1 敲除 (PC-KO) 小鼠来确定 NOXA1/NOX1 信号在 ANG II 依赖性 ENaC 激活中的作用。使用电压钳电生理学在新鲜分离的劈开小管中定量测量主细胞腔膜上 ENaC 的活性。ANG II 显著增加 ENaC 活性。这种作用是稳健的，并且在分别对分离的小管和小鼠进行急性（40 分钟）和更慢性（48-72 小时）ANG II 处理时都观察到。用氯沙坦抑制 ANG II 1 型受体可消除 ANG II 对 ENaC 的刺激作用。同样，用 NOX1 的特异性抑制剂 ML171 处理也可消除 ANG II 对 ENaC 的刺激作用。在从 PC-KO 小鼠分离的小管中，ANG II 处理未能增加 ENaC 活性。然而，野生型同窝对照的小管仍然能够通过增加 ENaC 活性对 ANG II 作出反应。这些结果表明，NOXA1/NOX1 信号介导了 ANG II 对肾脏主细胞 ENaC 的刺激作用。因此，远端肾单位中的 NOXA1/NOX1 信号在钠稳态和血压控制中发挥核心作用，尤其是与肾素-ANG II 轴的调节有关。
