Hypomagnesemia-induced Hypokalemia Is Associated with Higher Activities of ENaC and ROMK

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+ has been proposed to release Mg2+-mediated inhibition of renal outer medullary K+ (ROMK) channels, increasing urinary K+ excretion. However, hypomagnesemia alone is not suffcient to cause hypokalemia. Higher activity of the epithelial Na+ channel (ENaC), which provides the driving force for K+ secretion via ROMK, has been proposed to be an additional requirement. We tested the hypothesis that hypomagnesemia-induced hypokalemia is associated with higher activities of ENaC and ROMK. Methods: C57/BL6 mice were fed normal (NL) [Mg2+ 0.15%/NaCl ~0.49% (wt/wt)], low Mg2+ (LM) [Mg2+ 0.0015– 0.003% (wt/wt); NaCl ~0.49%], low sodium (LS) [Na+ <0.001% (wt/wt)], or combined low sodium and low Mg2+ (LS/LM) [Mg2+ 0.0015-0.003%/Na+ <0.001% (wt/wt)] diets for 3 or 7 days. All diets contained diet [K+ ~0.8% (wt/wt)]. Kidneys and blood were harvested for Western blotting and measurement of plasma [K+]. DCT2/CNT from mice on NL or LS/LM diet were microdissected for measurement of ROMK activity via patch-clamping of split open tubules. Results: Plasma [K+] was only significantly lower than in mice on NL diet in mice on LS/LM diet. Abundances of cleaved α- and γ-ENaC, which correlate with ENaC activity, were lower on a LM diet compared with NL diet. Consistent with lower ENaC activity, the urinary Na+:K+ ratio following acute amiloride administration was lower in mice on LM diet than in mice on NL. While abundances of cleaved α- and γ-ENaC abundances were higher on LS diet than on LS/LM or NL diets, they did not differ between mice on LS/LM or NL diets. As expected, mice on LS diet displayed higher plasma aldosterone than mice on NL diet, but plasma aldosterone did not differ between mice on LS/LM or control diets. ROMK activity along DCT2/CNT was higher in mice on LS/LM diet than compared with mice on NL diet. Conclusions: While LM diet lowered and LS diet stimulated ENaC cleavage compared with controls, ENaC cleavage was similar in mice on LS/LM or NL diets, suggesting dietary Na+ and Mg2+ deficiency counteract each other with regard to ENaC activation. Other studies have shown that the inhibitory effect of hypokalemia on aldosterone secretion may be more potent than the effect of volume depletion on promoting aldosterone secretion, which may explain the lower plasma aldosterone in mice on LS/LM diet than in mice on LS diet. Overall, our data suggest that both ENaC and disinhibition of ROMK are required for the development of hypokalemia in the context of hypomagnesemia. Y.M., Uehara Foundation; J.M., NIDDK DK132066; W-H.W., NIDDK DK133220. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.