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Abstract: TH-PO349

Dietary Magnesium Ion (Mg2+) Restriction Reduces Epithelial Sodium Channel (ENaC) Activity

Session Information

Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders

  • 1001 Fluid‚ Electrolyte‚ and Acid-Base Disorders: Basic


  • Maeoka, Yujiro, Oregon Health & Science University, Portland, Oregon, United States
  • Sharma, Avika, Oregon Health & Science University, Portland, Oregon, United States
  • Nguyen, Luan The, Oregon Health & Science University, Portland, Oregon, United States
  • McCormick, James A., Oregon Health & Science University, Portland, Oregon, United States

Hypokalemia occurs in 40 to 60% of patients with hypomagnesemia, and can result in cardiac arrhythmia and sudden death. Along the distal nephron, a decrease in intracellular Mg2+ releases the Mg2+-mediated inhibition of renal outer medullary K+ (ROMK) channels and increases K+ secretion. However, several animal studies have shown that hypomagnesemia alone cannot cause hypokalemia. Epithelial sodium channel (ENaC)-mediated sodium entry provides the driving force for K+ secretion via ROMK, but how hypomagnesemia affects ENaC activity remains unknown. We tested the hypotheses that (i) dietary Mg2+ restriction lowers ENaC activity, maintaining K+ homeostasis, and (ii) combined Mg2+/Na+ restriction activates ENaC, causing hypokalemia.


To assess ENaC activity during Mg2+ restriction, we performed Western blot for ENaC and an amiloride response test using C57/BL6 mice fed normal (NL) [Mg2+ 0.15% (wt/wt); NaCl ~0.49%] or low Mg2+ (LM) [Mg2+ 0.0015–0.003% (wt/wt); NaCl ~0.49%] diets for 3 days. To evaluate the interaction with low Na+ intake, which stimulates aldosterone secretion, we analyzed plasma [K+] and ENaC activity using mice fed NL or combined low sodium and low Mg2+ (LS/LM) [Mg2+ 0.0015–0.003% (wt/wt), Na+ ~0.000007%] diets for 7 days. K+ content was the same in each diet [K+ ~0.8% (wt/wt)].


The abundances of cleaved α- and γ-ENaC, which correlate with ENaC activity, were lower on a LM diet compared with NL diet. Amiloride response test showed a milder natriuretic effect on a LM diet, suggesting lower ENaC activity. In addition, plasma [Mg2+] correlated with cleaved α-ENaC abundance, but not plasma [K+] levels. In contrast, mice fed a LS/LM diet exhibited lower plasma [K+] levels compared with mice fed NL or LS diets. Cleaved α- and γ-ENaC abundances on LS/LM diet were similar to NL diet.


Together, these suggest that ENaC activity is lower following dietary Mg2+ restriction but higher with combined Mg2+/Na+ restriction, suggesting higher plasma aldosterone is required to stimulate K+ secretion. This likely explains why Mg2+ restriction alone cannot cause hypokalemia in vivo, and provides new insights into the mechanisms of hypomagnesemia-induced hypokalemia.


  • NIDDK Support