Kidney Week

Abstract: TH-PO349

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

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders

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

Authors

• Maeoka, Yujiro, Oregon Health & Science University, Portland, Oregon, United States

Yujiro Maeoka,

• Sharma, Avika, Oregon Health & Science University, Portland, Oregon, United States

Avika Sharma,

• Nguyen, Luan The, Oregon Health & Science University, Portland, Oregon, United States

Luan The Nguyen,

• McCormick, James A., Oregon Health & Science University, Portland, Oregon, United States

James A. McCormick,

Background

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.

Methods

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)].

Results

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.

Conclusion

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.

Funding

• NIDDK Support