NYMC Faculty Publications

Mg2+ Restriction Downregulates NCC Through NEDD4-2 and Prevents its Activation by Hypokalemia

Journal Title

American Journal of Physiology.Renal Physiology

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Publication Date

October 2019




Hypomagnesemia is associated with reduced kidney function and life-threatening complications, and sustains hypokalemia. The distal convoluted tubule (DCT) determines final urinary Mg(2+) excretion, and via activity of the Na(+)-Cl(-) cotransporter (NCC) also plays a key role in K(+) homeostasis by metering Na(+) delivery to distal segments. Little is known about the mechanisms by which plasma [Mg(2+)] regulates NCC activity, and how low plasma [Mg(2+)] and [K(+)] interact to modulate NCC activity. To address this we performed dietary manipulation studies in mice. Compared with normal diet, abundances of total NCC (tNCC) and phosphorylated NCC (pNCC) were lower following short-term (3 days) or long-term (14 days) dietary Mg(2+) restriction. Altered NCC activation is unlikely to play a role since we also observed lower tNCC abundance in mice lacking the two NCC-activating kinases SPAK and OSR1 following Mg(2+) restriction. The E3 ubiquitin-protein ligase NEDD4-2 regulates NCC abundance during dietary NaCl loading or K(+) restriction. Mg(2+) restriction did not lower tNCC abundance in inducible nephron-specific NEDD4-2 knockout mice. tNCC and pNCC abundances were similar following short-term Mg(2+) or combined Mg(2+)-K(+) restriction, but were dramatically lower compared with low K(+) diet. Sustained NCC downregulation may therefore serve a mechanism that enhances distal Na(+) delivery during states of hypomagnesemia, maintaining hypokalemia. Similar results were obtained with long-term Mg(2+)-K(+) restriction, but surprisingly, NCC was not activated following long-term K(+) restriction despite lower plasma [K(+)], suggesting significant differences in distal tubule adaptation to acute versus chronic K(+) restriction.