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Role of Basolateral K ir 4.1/K ir 5.1 Channel in the Regulation of Electrolyte Balance and ENaC Activity in the Cortical Collecting Duct
Author(s) -
Isaeva Elena,
Bohovyk Ruslan,
Fedoriuk Mykhailo,
Shalygin Alexey,
Klemens Christine,
Zietara Adrian,
Levchenko Vladislav,
Denton Jerod,
Staruschenko Alexander,
Palygin Oleg
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02816
Subject(s) - epithelial sodium channel , amiloride , chemistry , homeostasis , depolarization , endocrinology , apical membrane , medicine , biophysics , pharmacology , sodium , biochemistry , membrane , biology , organic chemistry
Recent genetic studies identified a critical role of basolateral inwardly rectifying K + (K ir ) channels of the distal nephron in K + homeostasis and blood pressure control, making these channels attractive targets for hypertension treatment. The main aim of the present study was to examine the effect of established and newly discovered inhibitors of basolateral K ir channels amitriptyline, fluoxetine, and VU0134992 on the epithelial sodium channel (ENaC) activity in the cortical collecting duct (CCD). We show that inhibition of heteromeric K ir 4.1/K ir 5.1, but not homomeric K ir 4.1 channel, substantially suppressed both amiloride‐sensitive equivalent short‐circuit current in cultured polarized epithelial mCCD cl1 cells and single‐channel ENaC activity in principal cells of rat and human CCD tubules. Using the combination of confocal microscopy, FluoVolt™ voltage‐sensitive dye, and Fluo8HT Ca 2+ dye, we show that acute application of amitriptyline or VU992 in concentrations that produce an inhibitory effect on K ir 4.1/K ir 5.1 channel resulted in substantial depolarization of cellular membrane potential and increase in intracellular Ca 2+ level in mCCD cl1 cells that can explain a significant decrease of ENaC open probability without altering channel conductance induced by these drugs. Furthermore, we evaluated the effect of nonspecific K ir inhibitor amitriptyline on electrolyte homeostasis and apical Na + transporters' expression in the distal nephron in Dahl salt‐sensitive (SS) rats. The administration of amitriptyline for three days led to a significant drop in plasma K + , an increase in Na + and K + excretion, and diuresis. These changes were accompanied by the compensatory overexpression of ENaC and total and phosphorylated forms of thiazide‐sensitive Na + ‐Cl ‐ ‐ cotransporter. Our data uncovered the putative mechanism of the impact of basolateral K ir 4.1/K ir 5.1 channel inhibition on ENaC activity and further emphasized a specific role of this channel in regulation of blood K + level and electrolyte homeostasis.