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Basic Research
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Kir4.1/Kir5.1 Activity Is Essential for Dietary Sodium Intake–Induced Modulation of Na-Cl Cotransporter

Peng Wu, Zhong-Xiuzi Gao, Xiao-Tong Su, Ming-Xiao Wang, Wen-Hui Wang and Dao-Hong Lin
JASN February 2019, 30 (2) 216-227; DOI: https://doi.org/10.1681/ASN.2018080799
Peng Wu
Department of Pharmacology, New York Medical College, Valhalla, New York
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Zhong-Xiuzi Gao
Department of Pharmacology, New York Medical College, Valhalla, New York
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Xiao-Tong Su
Department of Pharmacology, New York Medical College, Valhalla, New York
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Ming-Xiao Wang
Department of Pharmacology, New York Medical College, Valhalla, New York
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Wen-Hui Wang
Department of Pharmacology, New York Medical College, Valhalla, New York
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Dao-Hong Lin
Department of Pharmacology, New York Medical College, Valhalla, New York
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Significance Statement

Considerable evidence indicates that basolateral inwardly rectifying potassium channel Kir4.1/Kir5.1 is essential for membrane transport in the distal convoluted tubule (DCT), and that dietary sodium and potassium are important in regulating activity of the thiazide-sensitive Na-Cl cotransporter (NCC). In mouse studies, the authors found that stimulation of NCC induced by sodium restriction was associated with increasing Kir4.1/Kir5.1 activity in the DCT and membrane hyperpolarization; NCC inhibition induced by high sodium intake was associated with decreasing Kir4.1/Kir5.1 activity in the DCT and membrane depolarization. In kidney-specific Kir4.1 knockout mice, the effect of dietary sodium on NCC activity was largely abolished, as were its effects on DCT membrane conductance and potential. The findings indicate that Kir4.1/Kir5.1 is essential for mediating dietary sodium intake–induced modulation of NCC function.

Abstract

Background Dietary sodium intake regulates the thiazide-sensitive Na-Cl cotransporter (NCC) in the distal convoluted tubule (DCT). Whether the basolateral, inwardly rectifying potassium channel Kir4.1/Kir5.1 (a heterotetramer of Kir4.1/Kir5.1) in the DCT is essential for mediating the effect of dietary sodium intake on NCC activity is unknown.

Methods We used electrophysiology, renal clearance techniques, and immunoblotting to examine effects of Kir4.1/Kir5.1 in the DCT and NCC in wild-type and kidney-specific Kir4.1 knockout mice.

Results Low sodium intake stimulated basolateral Kir4.1/Kir5.1 activity, increased basolateral K+ conductance, and hyperpolarized the membrane. Conversely, high sodium intake inhibited the potassium channel, decreased basolateral K+ currents, and depolarized the membrane. Low sodium intake increased total and phosphorylated NCC expression and augmented hydrochlorothiazide-induced natriuresis; high sodium intake had opposite effects. Thus, elevated NCC activity induced by low sodium intake was associated with upregulation of Kir4.1/Kir5.1 activity in the DCT, whereas inhibition of NCC activity by high sodium intake was associated with diminished Kir4.1/Kir5.1 activity. In contrast, dietary sodium intake did not affect NCC activity in knockout mice. Further, Kir4.1 deletion not only abolished basolateral K+ conductance and depolarized the DCT membrane, but also abrogated the stimulating effects induced by low sodium intake on basolateral K+ conductance and hyperpolarization. Finally, dietary sodium intake did not alter urinary potassium excretion rate in hypokalemic knockout and wild-type mice.

Conclusions Stimulation of Kir4.1/Kir5.1 by low intake of dietary sodium is essential for NCC upregulation, and inhibition of Kir4.1/Kir5.1 induced by high sodium intake is a key step for downregulation of NCC.

  • potassium channels
  • epithelial sodium transport
  • hypertension
  • Copyright © 2019 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 30 (2)
Journal of the American Society of Nephrology
Vol. 30, Issue 2
February 2019
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Kir4.1/Kir5.1 Activity Is Essential for Dietary Sodium Intake–Induced Modulation of Na-Cl Cotransporter
Peng Wu, Zhong-Xiuzi Gao, Xiao-Tong Su, Ming-Xiao Wang, Wen-Hui Wang, Dao-Hong Lin
JASN Feb 2019, 30 (2) 216-227; DOI: 10.1681/ASN.2018080799

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Kir4.1/Kir5.1 Activity Is Essential for Dietary Sodium Intake–Induced Modulation of Na-Cl Cotransporter
Peng Wu, Zhong-Xiuzi Gao, Xiao-Tong Su, Ming-Xiao Wang, Wen-Hui Wang, Dao-Hong Lin
JASN Feb 2019, 30 (2) 216-227; DOI: 10.1681/ASN.2018080799
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Keywords

  • potassium channels
  • epithelial sodium transport
  • hypertension

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