Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto 604-8472, Japan.
Okamura Dental Clinic, Chuo-ku, Osaka 541-0041, Japan.
Int J Mol Sci. 2020 May 12;21(10):3407. doi: 10.3390/ijms21103407.
Epithelial Na channel (ENaC) participates in renal epithelial Na reabsorption, controlling blood pressure. Aldosterone and insulin elevate blood pressure by increasing the ENaC-mediated Na reabsorption. However, little information is available on the interactive action of aldosterone and insulin on the ENaC-mediated Na reabsorption. In the present study, we tried to clarify if insulin would modify the aldosterone action on the ENaC-mediated Na reabsorption from a viewpoint of intracellular ENaC trafficking. We measured the ENaC-mediated Na transport as short-circuit currents using a four-state mathematical ENaC trafficking model in renal A6 epithelial cells with or without aldosterone treatment under the insulin-stimulated and -unstimulated conditions. We found that: (A) under the insulin-stimulated condition, aldosterone treatment (1 µM for 20 h) significantly elevated the ENaC insertion rate to the apical membrane ( k I ) 3.3-fold and the ENaC recycling rate ( k R ) 2.0-fold, but diminished the ENaC degradation rate ( k D ) 0.7-fold without any significant effect on the ENaC endocytotic rate ( k E ); (B) under the insulin-unstimulated condition, aldosterone treatment decreased k E 0.5-fold and increased k R 1.4-fold, without any significant effect on k I or k D . Thus, the present study indicates that: (1) insulin masks the well-known inhibitory action of aldosterone on the ENaC endocytotic rate; (2) insulin induces a stimulatory action of aldosterone on ENaC apical insertion and an inhibitory action of aldosterone on ENaC degradation; (3) insulin enhances the aldosterone action on ENaC recycling; (4) insulin has a more effective action on diminution of ENaC endocytosis than aldosterone.
上皮钠通道（ENaC）参与肾脏上皮钠重吸收，控制血压。醛固酮和胰岛素通过增加 ENaC 介导的钠重吸收来升高血压。然而，关于醛固酮和胰岛素对 ENaC 介导的钠重吸收的相互作用的信息很少。在本研究中，我们试图从 ENaC 细胞内运输的角度阐明胰岛素是否会改变醛固酮对 ENaC 介导的钠重吸收的作用。我们使用四状态数学 ENaC 运输模型，在胰岛素刺激和非刺激条件下，测量肾 A6 上皮细胞中 ENaC 介导的钠转运作为短路电流，同时有或没有醛固酮处理。我们发现：（A）在胰岛素刺激条件下，醛固酮处理（1µM，20 小时）使 ENaC 向顶端膜的插入率（ k I ）显著增加 3.3 倍，ENaC 循环率（ k R ）增加 2.0 倍，但 ENaC 降解率（ k D ）降低 0.7 倍，对 ENaC 内吞率（ k E ）没有任何显著影响；（B）在胰岛素非刺激条件下，醛固酮处理使 k E 降低 0.5 倍，k R 增加 1.4 倍，对 k I 或 k D 没有显著影响。因此，本研究表明：（1）胰岛素掩盖了醛固酮对 ENaC 内吞率的众所周知的抑制作用；（2）胰岛素诱导醛固酮对 ENaC 顶端插入的刺激作用和对 ENaC 降解的抑制作用；（3）胰岛素增强了醛固酮对 ENaC 循环的作用；（4）胰岛素对 ENaC 内吞的抑制作用比醛固酮更有效。
