TY - JOUR
T1 - NOXA1-dependent NADPH oxidase 1 signaling mediates angiotensin II activation of the epithelial sodium channel
AU - Mironova, Elena
AU - Archer, Crystal R.
AU - Vendrov, Aleksandr E.
AU - Runge, Marschall S.
AU - Madamanchi, Nageswara R.
AU - Arendshorst, William J.
AU - Stockand, James D.
AU - Abd El-Aziz, Tarek Mohamed
N1 - Funding Information:
This work was supported by National Heart, Lung, and Blood Institute Grant R01HL139841 (to W.J.A. and N.R.M.).
Publisher Copyright:
Copyright © 2022 the American Physiological Society.
PY - 2022/12
Y1 - 2022/12
N2 - The activity of the epithelial Naþ channel (ENaC) in principal cells of the distal nephron fine-tunes renal Naþ excretion. The renin-angiotensin-aldosterone system modulates ENaC activity to control blood pressure, in part, by influencing Naþ 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-Noxa1 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-Noxa1 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 Naþ homeostasis and control of blood pressure, particularly as it relates to regulation by the renin-ANG II axis.
AB - The activity of the epithelial Naþ channel (ENaC) in principal cells of the distal nephron fine-tunes renal Naþ excretion. The renin-angiotensin-aldosterone system modulates ENaC activity to control blood pressure, in part, by influencing Naþ 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-Noxa1 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-Noxa1 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 Naþ homeostasis and control of blood pressure, particularly as it relates to regulation by the renin-ANG II axis.
KW - collecting duct
KW - hypertension
KW - reactive oxygen species
KW - renal physiology
KW - sodium excretion
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U2 - 10.1152/ajprenal.00107.2022
DO - 10.1152/ajprenal.00107.2022
M3 - Article
C2 - 36201326
AN - SCOPUS:85142918665
SN - 0363-6127
VL - 323
SP - F633-F641
JO - American journal of physiology. Renal physiology
JF - American journal of physiology. Renal physiology
IS - 6
ER -