Potassium intake modulates the thiazide-sensitive sodium-chloride cotransporter (NCC) activity via the Kir4.1 potassium channel

Wang, Ming Xiao; Cuevas, Catherina A.; Su, Xiao Tong; Wu, Peng; Gao, Zhong‐Xiuzi; Lin, Dao; McCormick, James A.; Yang, Chao; Wang, Wen Hui; Ellison, David H.

doi:10.1016/j.kint.2017.10.023

Cited by 118 publications

(147 citation statements)

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“…The [K] o affected the activity of WNK4/SPAK/NCC signaling and its downstream targets in this model cell line as determined by measuring the levels of pWNK4, pSPAK, and pNCC level, respectively. The inverse effect of increasing [K + ] o on pWNK4 levels in cells expressing wild-type WNK4 was abolished by K channel blockers (tertiapin and Ba 2+ ), thus confirming that DCT K channels (such as KCNJ10) are the route for K entry into these cells, which facilitates the subsequent effects on the WNK4/SPAK/NCC pathway as observed in in vivo studies (Wang et al, 2018). The absence of a similar K + sensitivity to the phosphorylation states of the same proteins in cells expressing the Cl − insensitive mutants, WNK4 LLFF and WNK4 LF KD respectively, emphasises the importance of the WNK4 Cl − binding and kinase domains for transducing the membrane potential changes caused by altered [K + ] o .…”

Section: Discussionsupporting

confidence: 65%

Modified HEK cells simulate DCT cells in their sensitivity and response to changes in extracellular K

Murthy

O’Shaughnessy

2019

Physiol Rep

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A potassium (K+) rich diet is known to have an antihypertensive effect that has been embodied by the NHLBI in the DASH diet. However, the molecular basis for this blood pressure‐lowering effect has been unclear, until a recent study proposed a model in which the DCT cells of the kidney regulate their salt transport in response to variations in intracellular chloride ([Cl−]i), which are directly regulated by serum K+. With the knowledge that WNK proteins are Cl− sensors, and are a part of the WNK/SPAK/NCC signaling cascade which regulates the NCC, the main salt transporter in the distal nephron, we examined the effect of serum K+ on the ([Cl−]i) and, in turn its effect on the WNK4 signaling pathway in a “modified HEK 293T” cell line. Using a fluorescence‐based approach in this cell line, we have shown that the membrane potential of the cell membrane is sensitive to the small changes in external KCl within the physiological range (2–5 mM), thus functioning as a K+ electrode. When the extracellular K+ was progressively increased (2–5 mM), the membrane depolarization lead to a subsequent increase in [Cl−]i measured by fluorescence quenching of an intracellular chloride sensor. Increase in extracellular [K] resulted in a decrease in the phosphorylation of the WNK4 protein and its downstream targets, SPAK and NCC. This confirms that small changes in serum K can affect WNK4/SPAK/NCC signaling and transcellular Na+ flux through the DCT and provide a possible mechanism by which a K‐rich DASH diet could reduce blood pressure.

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Section: Discussionsupporting

confidence: 65%

Modified HEK cells simulate DCT cells in their sensitivity and response to changes in extracellular K

Murthy

O’Shaughnessy

2019

Physiol Rep

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“…The Effect of LS or HS Intake on NCC Is Compromised in Ks-Kir4.1 KO Mice Previous studies have demonstrated that a hyperpolarization in the DCT is associated with an increase in NCC activity, whereas a depolarization of the DCT is associated with a decrease in NCC activity. [14][15][16] After demonstrating that the deletion of Kir4.1 abolished the effect of dietary Na + intake on the basolateral K + conductance and DCTmembrane potential, we suspect that the effect of dietary Na + intake on NCC should be absent or attenuated in Ks-Kir4.1 KO mice. Thus, we next examined the effect of dietary Na + intake on NCC in WT and Ks-Kir4.1 KO mice on LS, NS, and HS diets for 7 days (four male and three female mice for each group).…”

Section: Resultsmentioning

confidence: 99%

“…15 A large body of evidence has convincingly demonstrated that dietary Na + and K + intake play an important role in the regulation of NCC activity: low potassium or low sodium (LS) intake stimulates whereas high potassium or high sodium (HS) intake inhibits NCC activity. [14][15][16][20][21][22][23] Furthermore, our previous experiments have demonstrated that Kir4.1 plays a key role in mediating the effect of dietary K + intake on NCC because the deletion of Kir4.1 completely abolished the effect of dietary K + intake on NCC. 16 Thus, it raises the possibility whether Kir4.1 in the DCT is also involved in mediating the effect of dietary Na + intake on the thiazide-sensitive NCC.…”

mentioning

confidence: 91%

“…[14][15][16][20][21][22][23] Furthermore, our previous experiments have demonstrated that Kir4.1 plays a key role in mediating the effect of dietary K + intake on NCC because the deletion of Kir4.1 completely abolished the effect of dietary K + intake on NCC. 16 Thus, it raises the possibility whether Kir4.1 in the DCT is also involved in mediating the effect of dietary Na + intake on the thiazide-sensitive NCC. Therefore, the aim of this study is to test the hypothesis that LS intake-induced stimulation of NCC requires the activation of basolateral Kir4.1 in the DCT, whereas HS intake-induced inhibition of NCC requires the suppression of Kir4.1 activity.…”

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confidence: 91%

“…13 A large body of evidence indicates that the basolateral Kir4.1 in the DCT is essential for the membrane transport in the DCT. [13][14][15][16] Loss-of-function mutations of Kir4.1 in the kidney mainly impair the membrane transport in the DCT. [17][18][19] The role of Kir4.1 in mediating membrane transport in the DCT is recapitulated in Ks-Kir4.1 knockout mice with mild salt wasting, metabolic alkalosis, and hypokalemia due to the inhibition of NCC activity.…”

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confidence: 99%

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

Gao

et al. 2018

JASN

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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.

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Renal Chloride Channels in Relation to Sodium Chloride Transport

Teulon

Planelles

Sepúlveda

et al. 2018

Comprehensive Physiology

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The many mechanisms governing NaCl absorption in the diverse parts of the renal tubule have been largely elucidated, although some of them, as neutral NaCl absorption across the cortical collecting duct or regulation through with‐no‐lysine (WNK) kinases have emerged only recently. Chloride channels, which are important players in these processes, at least in the distal nephron, are the focus of this review. Over the last 20‐year period, experimental studies using molecular, electrophysiological, and physiological/functional approaches have deepened and renewed our views on chloride channels and their role in renal function. Two chloride channels of the ClC family, named as ClC‐Ka and ClC‐Kb in humans and ClC‐K1 and ClC‐K2 in other mammals, are preponderant and play complementary roles: ClC‐K1/Ka is mainly involved in the building of the interstitial cortico‐medullary concentration gradient, while ClC‐K2/Kb participates in NaCl absorption in the thick ascending limb, distal convoluted tubule and the intercalated cells of the collecting duct. The two ClC‐Ks might also be involved indirectly in proton secretion by type A intercalated cells. Other chloride channels in the kidneys include CFTR, TMEM16A, and probably volume‐regulated LRRC8 chloride channels, whose function and molecular identity have not as yet been established. © 2019 American Physiological Society. Compr Physiol 9:301‐342, 2019.

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Potassium intake modulates the thiazide-sensitive sodium-chloride cotransporter (NCC) activity via the Kir4.1 potassium channel

Cited by 118 publications

References 43 publications

Modified HEK cells simulate DCT cells in their sensitivity and response to changes in extracellular K

Modified HEK cells simulate DCT cells in their sensitivity and response to changes in extracellular K

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

Renal Chloride Channels in Relation to Sodium Chloride Transport

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