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

Abstract

Kir4.1 in the distal convoluted tubule plays a key role in sensing plasma potassium and in modulating the thiazide-sensitive sodium-chloride cotransporter (NCC). Here we tested whether dietary potassium intake modulates Kir4.1 and whether this is essential for mediating the effect of potassium diet on NCC. High potassium intake inhibited the basolateral 40 pS potassium channel (a Kir4.1/5.1 heterotetramer) in the distal convoluted tubule, decreased basolateral potassium conductance, and depolarized the distal convoluted tubule membrane in Kcnj10flox/flox mice, herein referred to as control mice. In contrast, low potassium intake activated Kir4.1, increased potassium currents, and hyperpolarized the distal convoluted tubule membrane. These effects of dietary potassium intake on the basolateral potassium conductance and membrane potential in the distal convoluted tubule were completely absent in inducible kidney-specific Kir4.1 knockout mice. Furthermore, high potassium intake decreased, whereas low potassium intake increased the abundance of NCC expression only in the control but not in kidney-specific Kir4.1 knockout mice. Renal clearance studies demonstrated that low potassium augmented, while high potassium diminished, hydrochlorothiazide-induced natriuresis in control mice. Disruption of Kir4.1 significantly increased basal urinary sodium excretion but it abolished the natriuretic effect of hydrochlorothiazide. Finally, hypokalemia and metabolic alkalosis in kidney-specific Kir4.1 knockout mice were exacerbated by potassium restriction and only partially corrected by a high-potassium diet. Thus, Kir4.1 plays an essential role in mediating the effect of dietary potassium intake on NCC activity and potassium homeostasis.

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

“…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 .…”

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

“…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).…”

“…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.…”

“…[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.…”

“…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.…”