NYMC Faculty Publications

Hypomagnesaemia-Associated Hypokalaemia Requires Activation of Both Enac and ROMK

Author Type(s)

Faculty

DOI

10.1113/JP287704

Journal Title

Journal of Physiology

First Page

7365

Last Page

7382

Document Type

Article

Publication Date

11-15-2025

Department

Pharmacology

Keywords

epithelial sodium channels, hypokalaemia, kidney, magnesium, potassium channel

Disciplines

Medicine and Health Sciences

Abstract

Abstract: Hypokalaemia is common in hypomagnesaemic patients, but the in vivo mechanisms have not been determined. Along the distal nephron, lower intracellular Mg2+ has been proposed to release the Mg2+-mediated inhibition of renal outer medullary K+ (ROMK) channels, increasing urinary K+ excretion. Higher activity of the epithelial Na+ channel (ENaC), which provides the driving force for K+ secretion via ROMK, may also be required. We tested the hypothesis that hypomagnesaemia-induced hypokalaemia is associated with higher activities of both ENaC and ROMK. C57BL/6J mice were fed normal (NL), low Mg2+ (LM), low Na+ (LS) or low Na+/Mg2+ (LS/LM) diets. Kidneys and blood were harvested for western blotting and measurement of plasma [K+]. ROMK activity was measured by patch-clamping of split-open distal convoluted tubule 2 (DCT2)/connecting tubule (CNT) from mice on NL or LS/LM diets. Plasma [K+] was significantly lower in mice on LS/LM diet. Compared with mice on NL diet, abundances of cleaved α- and γ-ENaC, which correlate with ENaC activity, were higher in mice on LS diet, and lower in mice on LM diet but not on LS/LM diet, suggesting Na+ and Mg2+ restriction counteract each other. A lower natriuretic response to acute amiloride administration confirmed lower ENaC activity in mice on LM diet. ROMK activity along DCT2/CNT was higher in mice on LS/LM but not on LM diet compared with mice on NL diet. Together, our data suggest that Mg2+ restriction inhibits ENaC activity, and both higher ENaC activity and disinhibition of ROMK are required for the development of hypokalaemia in the context of hypomagnesaemia. (Figure presented.). Key points: In patch-clamping experiments, lower intracellular Mg2+ releases the Mg2+-mediated inhibition of renal outer medullary K+ (ROMK) channels, increasing urinary K+ excretion, but hypomagnesaemia does not always lead to hypokalaemia in several genetic disorders and animal experiments. Epithelial sodium channel (ENaC)-mediated Na+ entry provides the driving force for K+ secretion via ROMK, but how hypomagnesaemia affects ENaC activity remains unknown. We found that ENaC activity is lower following dietary Mg2+ restriction but is preserved with combined Mg2+/Na+ restriction, stimulating K+ secretion via ROMK. Our findings probably explain why Mg2+ restriction alone cannot cause hypokalaemia in vivo and provide new insights into the mechanisms of hypomagnesaemia-induced hypokalaemia.

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