Titre
Mg<sup>2+</sup> restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Auteur(s)
Ferdaus, M.Z.
Auteure/Auteur
Mukherjee, A.
Auteure/Auteur
Nelson, J.W.
Auteure/Auteur
Blatt, P.J.
Auteure/Auteur
Miller, L.N.
Auteure/Auteur
Terker, A.S.
Auteure/Auteur
Staub, O.
Auteure/Auteur
Lin, D.H.
Auteure/Auteur
McCormick, J.A.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1522-1466
Statut éditorial
Publié
Date de publication
2019-10-01
Volume
317
Numéro
4
Première page
F825
Dernière page/numéro d’article
F838
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
Hypomagnesemia is associated with reduced kidney function and life-threatening complications and sustains hypokalemia. The distal convoluted tubule (DCT) determines final urinary Mg <sup>2+</sup> excretion and, via activity of the Na <sup>+</sup> -Cl <sup>-</sup> cotransporter (NCC), also plays a key role in K <sup>+</sup> homeostasis by metering Na <sup>+</sup> delivery to distal segments. Little is known about the mechanisms by which plasma Mg <sup>2+</sup> concentration regulates NCC activity and how low-plasma Mg <sup>2+</sup> concentration and K <sup>+</sup> concentration interact to modulate NCC activity. To address this, we performed dietary manipulation studies in mice. Compared with normal diet, abundances of total NCC and phosphorylated NCC (pNCC) were lower after short-term (3 days) or long-term (14 days) dietary Mg <sup>2+</sup> restriction. Altered NCC activation is unlikely to play a role, since we also observed lower total NCC abundance in mice lacking the two NCC-activating kinases, STE20/SPS-1-related proline/alanine-rich kinase and oxidative stress response kinase-1, after Mg <sup>2+</sup> restriction. The E3 ubiquitin-protein ligase NEDD4-2 regulates NCC abundance during dietary NaCl loading or K <sup>+</sup> restriction. Mg <sup>2+</sup> restriction did not lower total NCC abundance in inducible nephron-specific neuronal precursor cell developmentally downregulated 4-2 (NEDD4-2) knockout mice. Total NCC and pNCC abundances were similar after short-term Mg <sup>2+</sup> or combined Mg <sup>2+</sup> -K <sup>+</sup> restriction but were dramatically lower compared with a low-K <sup>+</sup> diet. Therefore, sustained NCC downregulation may serve a mechanism that enhances distal Na <sup>+</sup> delivery during states of hypomagnesemia, maintaining hypokalemia. Similar results were obtained with long-term Mg <sup>2+</sup> -K <sup>+</sup> restriction, but, surprisingly, NCC was not activated after long-term K <sup>+</sup> restriction despite lower plasma K <sup>+</sup> concentration, suggesting significant differences in distal tubule adaptation to acute or chronic K <sup>+</sup> restriction.
Sujets
PID Serval
serval:BIB_A3B2541B62F6
PMID
Date de création
2019-08-06T15:13:40.388Z
Date de création dans IRIS
2025-05-20T23:45:56Z