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The renal epithelium is sensitive to changes in blood potassium (K+). We identify the basolateral K+ channel, Kir4.2, as a mediator of the proximal tubule response to K+ deficiency. Mice lacking Kir4.2 have a compensated baseline phenotype whereby they increase their distal transport burden to maintain homeostasis. Upon dietary K+ depletion, knockout animals decompensate as evidenced by increased urinary K+ excretion and development of a proximal renal tubular acidosis. Potassium wasting is not proximal in origin but is caused by higher ENaC activity and depends upon increased distal sodium delivery. Three-dimensional imaging reveals Kir4.2 knockouts fail to undergo proximal tubule expansion, while the distal convoluted tubule response is exaggerated. AKT signaling mediates the dietary K+ response, which is blunted in Kir4.2 knockouts. Lastly, we demonstrate in isolated tubules that AKT phosphorylation in response to low K+ depends upon mTORC2 activation by secondary changes in Cl- transport. Data support a proximal role for cell Cl- which, as it does along the distal nephron, responds to K+ changes to activate kinase signaling. The renal epithelium is sensitive to changes in blood K+. Here, Zhang et al. identify low K+ as a potent activator of proximal tubule mTOR/AKT signaling, which occurs through the K+ channel, Kir4.2 to modulate epithelial cell growth and Na+ transport. [ABSTRACT FROM AUTHOR]

High K+ supplementation is correlated with a lower risk of the composite of death, major cardiovascular events, and ameliorated blood pressure, but the exact mechanisms have not been established. Inwardly rectifying K+ (Kir) channels expressed in the basolateral membrane of the distal nephron play an essential role in maintaining electrolyte homeostasis. Mutations in this channel family have been shown to result in strong disturbances in electrolyte homeostasis, among other symptoms. Kir7.1 is a member of the ATP-regulated subfamily of Kir channels. However, its role in renal ion transport and its effect on blood pressure have yet to be established. Our results indicate the localization of Kir7.1 to the basolateral membrane of aldosterone-sensitive distal nephron cells. To examine the physiological implications of Kir7.1, we generated a knockout of Kir7.1 (Kcnj13) in Dahl salt-sensitive (SS) rats and deployed chronic infusion of a specific Kir7.1 inhibitor, ML418, in the wild-type Dahl SS strain. Knockout of Kcnj13 (Kcnj13-/-) resulted in embryonic lethality. Heterozygous Kcnj13þ/- rats revealed an increase in K+ excretion on a normal-salt diet but did not exhibit a difference in blood pressure development or plasma electrolytes after 3 wk of a high-salt diet. Wild-type Dahl SS rats exhibited increased renal Kir7.1 expression when dietary K+ was increased. K+ supplementation also demonstrated that Kcnj13þ/- rats excreted more K+ on normal salt. The development of hypertension was not different when rats were challenged with high salt for 3 wk, although Kcnj13þ/- rats excrete less Na+. Interestingly, chronic infusion of ML418 significantly increased Na+ and Cl- excretion after 14 days of high salt but did not alter salt-induced hypertension development. Here, we found that reduction of Kir7.1 function, either through genetic ablation or pharmacological inhibition, can influence renal electrolyte excretion but not to a sufficient degree to impact the development of SS hypertension. [ABSTRACT FROM AUTHOR]

Background and Purpose: Inwardly rectifying K+ (Kir) channels located on the basolateral membrane of epithelial cells of the distal nephron play a crucial role in K+ handling and BP control, making these channels an attractive target for the treatment of hypertension. The purpose of the present study was to determine how the inhibition of basolateral Kir4.1/Kir5.1 heteromeric K+ channel affects epithelial sodium channel (ENaC)‐mediated Na+ transport in the principal cells of cortical collecting duct (CCD). Experimental Approach The effect of fluoxetine, amitriptyline and recently developed Kir inhibitor, VU0134992, on the activity of Kir4.1, Kir4.1/Kir5.1 and ENaC were tested using electrophysiological approaches in CHO cells transfected with respective channel subunits, cultured polarized epithelial mCCDcl1 cells and freshly isolated rat and human CCD tubules. To test the effect of pharmacological Kir4.1/Kir5.1 inhibition on electrolyte homeostasis in vivo and corresponding changes in distal tubule transport, Dahl salt‐sensitive rats were injected with amitriptyline (15 mg·kg−1·day−1) for 3 days. Key Results: We found that inhibition of Kir4.1/Kir5.1, but not the Kir4.1 channel, depolarizes the cell membrane, induces the elevation of intracellular Ca2+ concentration and suppresses ENaC activity. Furthermore, we demonstrate that amitriptyline administration leads to a significant drop in plasma K+ level, triggering sodium excretion and diuresis. Conclusion and Implications: The present data uncover a specific role of the Kir4.1/Kir5.1 channel in the modulation of ENaC activity and emphasize the potential for using Kir4.1/Kir5.1 inhibitors to regulate electrolyte homeostasis and BP. [ABSTRACT FROM AUTHOR]

High K + supplementation is correlated with a lower risk of the composite of death, major cardiovascular events, and ameliorated blood pressure, but the exact mechanisms have not been established. Inwardly rectifying K + (K ir ) channels expressed in the basolateral membrane of the distal nephron play an essential role in maintaining electrolyte homeostasis. Mutations in this channel family have been shown to result in strong disturbances in electrolyte homeostasis, among other symptoms. K ir 7.1 is a member of the ATP-regulated subfamily of K ir channels. However, its role in renal ion transport and its effect on blood pressure have yet to be established. Our results indicate the localization of K ir 7.1 to the basolateral membrane of aldosterone-sensitive distal nephron cells. To examine the physiological implications of K ir 7.1, we generated a knockout of K ir 7.1 ( Kcnj13 ) in Dahl salt-sensitive (SS) rats and deployed chronic infusion of a specific K ir 7.1 inhibitor, ML418, in the wild-type Dahl SS strain. Knockout of Kcnj13 ( Kcnj13 -/- ) resulted in embryonic lethality. Heterozygous Kcnj13 +/- rats revealed an increase in K + excretion on a normal-salt diet but did not exhibit a difference in blood pressure development or plasma electrolytes after 3 wk of a high-salt diet. Wild-type Dahl SS rats exhibited increased renal K ir 7.1 expression when dietary K + was increased. K + supplementation also demonstrated that Kcnj13 +/- rats excreted more K + on normal salt. The development of hypertension was not different when rats were challenged with high salt for 3 wk, although Kcnj13 +/- rats excrete less Na + . Interestingly, chronic infusion of ML418 significantly increased Na + and Cl - excretion after 14 days of high salt but did not alter salt-induced hypertension development. Here, we found that reduction of K ir 7.1 function, either through genetic ablation or pharmacological inhibition, can influence renal electrolyte excretion but not to a sufficient degree to impact the development of SS hypertension. NEW & NOTEWORTHY To investigate the role of the K ir 7.1 channel in salt-sensitive hypertension, its function was examined using complementary genetic and pharmacological approaches. The results revealed that although reducing K ir 7.1 expression had some impact on maintaining K + and Na + balance, it did not lead to a significant change in the development or magnitude of salt-induced hypertension. Hence, it is probable that K ir 7.1 works in conjunction with other basolateral K + channels to fine-tune membrane potential.

Background and Purpose: Inwardly rectifying K + (K ir ) channels located on the basolateral membrane of epithelial cells of the distal nephron play a crucial role in K + handling and BP control, making these channels an attractive target for the treatment of hypertension. The purpose of the present study was to determine how the inhibition of basolateral K ir 4.1/K ir 5.1 heteromeric K + channel affects epithelial sodium channel (ENaC)-mediated Na + transport in the principal cells of cortical collecting duct (CCD)., Experimental Approach: The effect of fluoxetine, amitriptyline and recently developed K ir inhibitor, VU0134992, on the activity of K ir 4.1, K ir 4.1/K ir 5.1 and ENaC were tested using electrophysiological approaches in CHO cells transfected with respective channel subunits, cultured polarized epithelial mCCD cl1 cells and freshly isolated rat and human CCD tubules. To test the effect of pharmacological K ir 4.1/K ir 5.1 inhibition on electrolyte homeostasis in vivo and corresponding changes in distal tubule transport, Dahl salt-sensitive rats were injected with amitriptyline (15 mg·kg -1 ·day -1 ) for 3 days., Key Results: We found that inhibition of K ir 4.1/K ir 5.1, but not the K ir 4.1 channel, depolarizes the cell membrane, induces the elevation of intracellular Ca 2+ concentration and suppresses ENaC activity. Furthermore, we demonstrate that amitriptyline administration leads to a significant drop in plasma K + level, triggering sodium excretion and diuresis., Conclusion and Implications: The present data uncover a specific role of the K ir 4.1/K ir 5.1 channel in the modulation of ENaC activity and emphasize the potential for using K ir 4.1/K ir 5.1 inhibitors to regulate electrolyte homeostasis and BP., (© 2021 The British Pharmacological Society.)