Chronic Potassium Adaptation Decreases Thiazide‐Sensitive Sodium Excretion with Preserved Potassium Excretion independent of NCC phosphorylation

Abstract

Acute increases in K intake decrease Na‐Cl cotransporter (NCC) phosphorylation and NCC‐mediated Na reabsorption. This decrease in NCC phosphorylation, coupled with increased distal delivery of Na and enhanced ENaC activity, is one mechanism to augment kaliuresis. We sought to dissect the role of adaptation to a high K diet in which the plasma K concentration was unchanged between a normal and high K diet. To test this, we measured thiazide‐sensitive electrolyte excretion in acutely fasted mice fed a chronic normal or high K diet with and without the addition of benzamil, an ENaC antagonist.We placed C57Bl/6J mice on either a normal (0.7% w/w) or high (5% w/w) K diet for 1 week. We fasted mice, performed an intraperitoneal injection of either 30 mg/kg hydrochlorothiazide to inhibit NCC, 1.4 mg/kg benzamil to inhibited ENaC, or both, and collected urine for 4 hours. After a washout period, we sacrificed mice after an acute fast for tissue analysis. We measured plasma aldosterone concentration from a separate, similarly treated group of normal or high K‐fed mice.Mice demonstrated decreased thiazide‐induced Na excretion on a high K diet compared to a normal K diet, yet thiazide‐induced K excretion remained unchanged (0.138 +/− 0.017 vs. 0.109 +/− 0.006 μmol/min, normal vs. high K diet, respectively, p=0.28) and significantly higher than vehicle. Aldosterone was significantly higher in the high K diet‐fed group (141 +/− 13 vs. 516 +/− 171 pg/ml, normal vs. high K diet, respectively; p<0.05). Benzamil increased urine flow on the high K (1.03 +/− 0.05 μl/min, p<0.05) but not normal K diet (0.42 +/− 0.19 μl/min, p=0.2) compared to vehicle (0.46 +/− 0.11 μl/min), congruent with increased ENaC‐mediated Na reabsorption. Plasma K concentrations in acutely fasted mice were no different between mice on normal or high K diets (4.98 +/− 0.22 vs. 4.53 +/− 0.17 mmol/L, normal vs. high K diet, respectively, p=0.2). Membrane preparations of kidney lysate blotted for total and phosphorylated NCC were not significantly different on a normal vs. high K diet. The increase in K excretion in high K diet‐fed mice after thiazide administration suggests that NCC activity is not significantly diminished. The decrease in thiazide‐induced Na excretion may be explained by an aldosterone‐mediated increase in ENaC activity with a chronic, high K diet. These data provide evidence that both NCC phosphorylation and activity are not tonically suppressed with high K adaptation in the absence of elevated plasma K concentrations. ENaC activity is also increased on a high K diet in the absence of elevated plasma K. Furthermore, plasma K‐mediated regulation of NCC phosphorylation may be relevant for short‐term, rather than chronic K adaptation.Support or Funding InformationJMN receives support from the NIH (1K08 DK114567‐01). JMN was previously supported by an American Heart Association Postdoctoral Fellowship (16POST27770003). VB receives support from the NIH (1R01 DK091565).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.