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Int J Mol Sci
2020 May 12;2110:. doi: 10.3390/ijms21103407.
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Interactive Actions of Aldosterone and Insulin on Epithelial Na+ Channel Trafficking.
Marunaka R
,
Marunaka Y
.
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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.
Figure 1. An intracellular ENaC trafficking model. (1) An insertion state (Insert): this state contains epithelial Na+ channel (ENaC) that accesses to the apical membrane with an insertion rate into the apical membrane (kI). (2) An apical membrane state (Apical): this state contains ENaC that functions as Na+-conducting (permeant) pathways across the apical membrane. (3) A recycling state (Recycl): this state contains ENaC retrieved from the apical membrane with an endocytotic rate (kE), and then the ENaC is trafficked back to the insertion state (Insert) with a recycling rate (kR), or moves to a degradation pathway (Degrad) with a degradation rate (kD).
Figure 2. Representative observations of experimentally measured insulin (100 nM)-stimulated short-circuit currents (ISC) and simulated ISC using a four-state mathematical model with and without treatment of aldosterone (ALDO, 1 µM for 20 h). (A) Blue squares and line respectively indicate a typical time course of experimentally measured insulin-stimulated ISC (blue squares) and a simulated time course of ISC (blue line) in cells with 1 µM aldosterone-treatment for 20 h. Red circles and line respectively indicate a typical time course of experimentally measured insulin-stimulated ISC (red circles) and a simulated time course of ISC (red line) in cells without aldosterone-treatment. (B) Normalized ISC to each peak value of ISC = 1. Blue squares and line respectively show the normalized measured ISC and simulated ISC in cells with 1 µM aldosterone-treatment for 20 h. Red circles and line respectively show the normalized measured ISC and simulated ISC in cells without aldosterone-treatment.
Figure 3. Insulin-induced time-dependent changes in the amounts of ENaC localized in four states, Insert, Apical, Recycl, and Degrad, shown in Figure 1 in cells treated with and without aldosterone (ALDO, 1 µM for 20 h). The amounts of ENaC localized in each state under aldosterone-treated and -untreated conditions are respectively shown by solid (with aldosterone treatment: ALDO (+)) and dot (without aldosterone treatment: ALDO (–)) lines. A, an insertion state (Insert); B, an apical membrane state (Apical); C, a recycling state (Recycl); D, a degradation state (Degrad) as shown in Figure 1. (A) Insert (t)
(blue lines) shows the amount of ENaC in an insertion state, Insert, at time = t: (B) Apical (t) (red lines), the amount of ENaC in an apical membrane state, Apical, at time = t: (C) Recycl (t)
(green lines), the amount of ENaC in a recycling state, Recycl, at time = t: (D) Degrad (t) (pink lines), the amount of ENaC in a degradation state, Degrad, at time = t. t is the time elapsed after application of 100 nM insulin to the basolateral solution. Insert (t), Apical (t), Recycl (t) and Degrad (t) respectively represented by Equations (5)–(8) are described using the values of kI, kE, kR, and kD determined by fitting Apical (t) to the experimentally measured ISC.
Figure 4. The action of aldosterone treatment (1 µM, 20 h) on the intracellular ENaC trafficking under the condition with (A) and without (B) stimulation by insulin (100 nM). (A) Under the insulin-stimulated condition, aldosterone treatment significantly elevated kI 3.3-fold and kR2.0-fold, but diminished kD 0.7-fold without any significant effect on kE. (B) Under the insulin-unstimulated condition, aldosterone treatment significantly decreased kE 0.5-fold and increased kR1.4-fold without any significant effect on kI
or kD
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